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Vitamin D and Diabetic Retinopathy

Int. J. Mol. Sci. 2023, 24(15), 12014; https://doi.org/10.3390/ijms241512014

by Antonela Gverović Antunica^1,*

, Ljubo Znaor², Mira Ivanković³, Velibor Puzović⁴, Irena Marković²

and Snježana Kaštelan⁵

Reviewer 1:

Francesca Lazzara

Reviewer 2:

Marco Zeppieri

Int. J. Mol. Sci. 2023, 24(15), 12014; https://doi.org/10.3390/ijms241512014

Submission received: 29 June 2023 / Revised: 23 July 2023 / Accepted: 25 July 2023 / Published: 27 July 2023

(This article belongs to the Special Issue The Molecular and Cellular Pathophysiologic Mechanisms Underlying Ocular Diseases and Emerging Therapies)

Round 1

Reviewer 1 Report

This review is interesting, the authors adequately describe vitamin D, DR and their link.

Just some observations from my side:

- line 62: the authors start to describe the process of production of the vitamin d active form, than they pick this up again at line 90. I suggest to put this parts together.

- I suggest to make subparagraph 2.1 as a new paragraph (n.3): vitamin D and DR

- in general, authors have to rearrange bibliography which is fundamental in a review; here there are too few references. Several sentences are missing ref, for example line 154, 155, 177 and many other. Moreover, line 184-186 where the authors could mention also this study: PMID: 36091806.

- line 221: why did the authors describe in this paragraph this pathway? Which is the link with vitamin D (it's in paragraph "Vitamin D and DR")? why did they decide to describe only this pathway?

- Are there any ongoing clinical trial? Could the authors mention something about ongoing clinical trials?

English language needs only minor editing.

Author Response

Answer to Reviewer 1

Dear Reviewer

The process production of the vitamin D active form is discribed at line 90, and deleted at line 62.
New paragraph N^O 3 is created instead subparagraph 2.1
New references have been added, as well as study PMID: 36091806.
We describe this pathway because oxidative stress is an important factor for DR, while vitamin D may also have an antioxidant effect through the inhibition of free radical. There is evidence that excessive production of reactive oxygen species (ROS) in the retina causes retinal damage by altering cellular signaling pathways.
Ongoing clinical trial are added in the article „In recent research, vitamin D is not only important in bone metabolism, but also as a strong antioxidant that significantly reduces the formation of free radicals, has an anti-inflammatory effect and modulates autophagy and apoptosis, so vitamin supplementation should be useful in reducing the damaging effects of free radicals in DR. „[69,70].
Fekri,S.; Soheilian, M.; Roozdar, S.; Abtahi, SH.; Nouri, H.The effect of vitamin D supplementation on the outcome of treatment with bevacizumab in diabetic macular edema: a randomized clinical trial. Int Ophthalmol. 2022, 42(11): 3345–3356.
Valle, MS.; Russo C.; Malaguarnera, L. Protective role of vitamin D against oxidative stress in diabetic retinopathy Diabetes Metab Res Rev.2021 Nov;37(8):e3447. doi: 10.1002/dmrr.3447. Epub 2021 Mar 24.

Reviewer 2 Report

The aim of the study entitled "Vitamin D and Diabetic Retinopathy" was to provide a review regarding the importance of Vitamin D in diabetic retinopathy. The topic is interesting and can be of potential clinical use, especially considering the increasing incidence of this disease worldwide.

The presentation of the paper is not formatted properly and does not flow well. There is no logical order or sequence to the review. The aim of the paper is not mentioned in the abstract. The introduction is not clear and does even not touch upon the purpose of the review and the aspects of diabetic retinopathy.

The table is informative and presents the important literature in this field. No mention, however, is made of how these papers were selected and the criteria used in the search strategies on PubMed or other sources. The table lacks order and is not clear if the authors are listing the papers ranked according to importance, cohort size, chronologic, etc. The description of the studies reported has been approached in a rather superficial manner. Relevant and pertinent details regarding the specific roles of vitamin D in diabetic retinopathy can be improved and better organized.

The authors should consider the clinical applications of the study by mentioning the possible benefits of nutrients and supplements to slow down the progression of the disease, supported by appropriate references. A simple flowchart on how to manage patients with diabetic retinopathy with the use of diagnostic tools and supplementation regarding vitamin D deficiency could render the review of clinical importance. Figures could be useful to describe specific underlying mechanisms. Mention of future prospective regarding clinical trials, diagnosis, management, and treatment in light of the potential importance of vitamin D in retinopathy should be included.

The text does not read well. A native English doctor's editing is needed to improve the English and flow of the manuscript.

Author Response

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

„Clinical studies have proven the effectiveness of vitamin D supplementation in the treatment of diabetic retinopathy, but with a doctor's recommendation and supervision due to possible negative side effects.“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

„The treatment of DR aims to slow down its progression, prevent vision loss, and improve visual function. The specific procedure of treatment may vary depending on the severity and stage of DR. General outline of the treatment procedure:

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

The choice of procedure is determined by the ophthalmologist according to the severity of the damage. It is important to note that the latest clinical trials have shown that the correction of VD in patients with diabetic macular edema can play an important role in improving macular edema, but the effect is visible only after a few months, so in diabetics, in addition to the regulation of blood glucose, hypertension and lipid levels, the level of VD should definitely be analyzed and, in case of reduced concentration, VD should be supplemented [68].

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Answers to Reviewer 2

Dear Reviewer

The aim of the paper is added in the abstract „Diabetic retinopathy (DR) is the most common eye disease complication of diabetes, and hypovitaminosis D is mentioned as one of the risk factors“

In introduction is added „Diabetic retinopathy is becoming a major health problem with possible serious complications, and limited normal functioning. Various risk factors are listed, as well as the correlation with vitamin D, and such findings are presented in this article. Several ways in which vitamin D may be linked to diabetic retinopathy are: anti-inflammatory effect. antioxidant effect, blood pressure regulation and impact on insulin sensitivity.“
The table has been rearranged, and the papers are listed in chronological order. All works are found in PubMed. Relevant details regarding the specific roles of VD in DR is

Table 2. Studies in relationship between VD and DR

First Author		Years		Country		Study-Design		Sample Size	Main Finding
Harleen Kaur [39]		2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus	Vitamin D VDdeficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy DRwas associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Snježana Kaštelan [29]		2013.		Croatia		Cross-sectional study		545 patients with type 2 diabetes.	Progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 ± 2.70, gr. 2: 28.11 ± 3.00, gr. 3: 28.69 ± 2.50; P < 0.01).
Martina Tomić [30]		2013.		Croatia		cross-sectional study		107 patients with type 2 diabetes	After dividing the patients according to the level of obesity (defined by BMI, WC, and WHR) into three groups ANOVA showed the differences in C-reactive protein according to the WC (P = 0.0265) and in fibrinogen according to the WHR (P = 0.0102) as well as in total cholesterol (P = 0.0109) and triglycerides (P = 0.0133) according to the BMI. Logistic regression analyses showed that diabetes duration and prolonged poor glycemic control are the main predictors of retinopathy in patients with type 2 diabetes.
Snježana Kaštelan [31]		2014		Croatia		Cross-sectional study		176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57).	DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01).
Giacomo Zoppini [35]		2015.		Italy		cross-sectional study,		715 outpatients with type 2 diabetes	Inverse and independent relationship between circulating 25(OH)D3 levels and the prevalence of microvascular complications in patients with T2DM.
Nuria Alcubierre [36]		2015.		Spain		observational case-control study.		Two groups of patients were selected: 139 and 144 patients with and without retinopathy	Study confirms the association of vitamin D deficiency with the presence and severity of diabetic retinopathy in type 2 diabetes.
G Bhanuprakash Reddy [56]		2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls	There are an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.
Adem Gungor [54]		2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients	Results suggest that vitamin D VD acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Markus Herrmann [41]		2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes	Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Wei-Jing Zhao [13]		2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus	Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
Beteal Ashinne [42]		2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus	A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Hülya Aksoy [38]		2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus	Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Harleen Kaur [15]	2011		Australia		Cross-sectional study		517 patients with type 1 diabetes mellitus		Vitamin D deficiency is associated with an increased prevalence of retinopathy in young people with T1DM. In a logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA1c (1.24, 1.02-1.50).
Markus Herrmann [16]	2015		Australia, New Zealand, and Finland		Multinational, double-blind, placebo-controlled trial		9795 patients with type 2 diabetes		Increased risk of macrovascular and microvascular disease events in T2DM are associated with low blood 25(OH)D₃.
Beteal Ashinne [18]	2018		India		Retrospective study		3054 patients with type 2 diabetes mellitus		A lower serum level of 25(OH)D3 was associated with a higher severity of DR, and the presence of vitamin D deficiency was associated with a twofold increased risk of PDR. A statistically significant difference in serum vitamin D mean levels of these categorizations: no DR (13.7 ± 2.1 ng/ml), non-sight threatening DR (12.8 ± 2.1 ng/mL ), vision threatening DR (11.1 ± 2.2 ng/mL ), (p < 0.001).
Abdulbari Bener [43]	2018		Turkey		Cross-sectional study		638 patients with type 3 diabetes mellitus		Vitamin D deficiency is considered a risk factor for DR and hearing loss in diabetics.
Gauhar Nadri [44]	2019		India		Cross-sectional study		72 patients with DM, 24 without DR, 24 with NPDR, and 24 with PDR		Serum vitamin D levels of ≤ 18.6 ng/mL serve as a sensitive and specific indicator of proliferative disease in patients of DR. Univariate ordinal logistic regression analysis revealed that vitamin D was VD is a significant predictor of diabetic retinopathy severity { OR (95% CI) = 1.11 (1.06-1.16) (p < 0.01 or p < 0.001)}. The ROC curve analysis showed that a vitamin D cut-off value of 18.6 ng/mL was significantly associated with NPDR and PDR.
Jing Yuan [45]	2019		China		Cross-sectional study		889 patients with type 2 diabetes		Vitamin D deficiency is significantly associated with risk of PDR. The odd ratio in individuals with vitamin D deficiency was significantly increased (1.84, 95% CI 1.18-2.86) for DR, 1.60 (95% CI 1.06-2.42) for PDR, compared with individuals with adequate vitamin D, after adjustment for age, sex, blood pressure, renal function, duration of diabetes, and HbA1c.
Abdulhalim Senyigit [46]	2019		Turkey		Cross-sectional study		163 patients with type 2 diabetes and 40 controls		Low serum 25-OHD levels have been found to be associated with the development of diabetes and complications. Serum 25(OH)D levels were significantly lower in all patients than in the control group (p < 0.05). The 25(OH)D levels of patients with complications were lower than those of patients without complications. (The p values for the nephropathy and retinopathy groups were < 0.001, whereas the value for the neuropathy group was < 0.01.) Low serum 25-OHD levels may be a consequence of even worse metabolic control of diabetes.
Hülya Aksoy [16]	2000		Turkey		Cross-sectional study		66 patients with type 2 diabetes mellitus		Inverse relationship between severity of retinopathy, neovascularization, and serum 1,25(OH)2D3 concentrations, which were lowest in PDR patients and highest in diabetic patients without retinopathy. Mean 1.25(OH)2D3 concentrations decreased with increasing severity of diabetic retinopathy. Only mean 1.25(OH)2D3 concentrations did not differ significantly between NDR and BDR, pre-PDR and PDR (p > 0.05). Mean 1.25(OH)2D3 concentrations differed significantly between the other groups (p < 0.05).
Adem Gungor [28]	2015		Turkey		Prospective study		50 VDD with DR patients and 50 VDD without DR patients		Results suggest that vitamin D acts as a neuroprotective component for optic nerves. Low serum 25(OH)D concentrations contribute to RNFL thinning in patients with early-stage VDD DR. The mean RNFL thickness of group 1 was significantly reduced compared to that of group 2 (p < 0.001). In group 1, a significant relationship was observed between mean RNFL thickness and serum 25(OH)D concentration (p < 0.001).
Ying Xiao [55]	2020		China		Cross-sectional study		4284 patients with type 2 diabetes mellitus		In unadjusted analyses, DR was associated with VDD status (PR: 1.147; 95% CI: 1.025-1.283), and the association remained after adjustment for age and sex and other demographic and physical measures. However, significance decreased after adjustment for all confounding factors (PR: 1.093; 95% CI: 0.983-1.215).
Wei-Jing Zhao [37]	2021.		China		Cross-sectional study,		815 patients with type 2 diabetes mellitus		Patients with type 2 diabetes and VD deficiency (serum 25(OH)D level below 20 ng/ml) have a significantly increased risk of DR.
G Bhanuprakash Reddy [30]	2015		India		Cross- sectional case-control study		82 T2DM with DR patients and 99 healthy controls		There may be an association between vitamin D deficiency and type 2 diabetes, but not specifically with retinopathy.

Treatment of DR is added

Medical Management

Proper blood sugar control, blood pressure management, and cholesterol control are essential to slow down the progression of the disease.

Laser Photocoagulation,
Anti-VEGF Injections,
Corticosteroid Implants,
Vitrectomy,
Other procedures ( vitamin supplementation)

Round 2

Reviewer 2 Report

The authors have addressed the issues raised in a sufficient manner.

The text still does not read well. A native English doctor's editing is needed to improve the English and flow of the manuscript.

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Vitamin D and Diabetic Retinopathy

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