Dietary Intake and Diabetic Retinopathy: A Systematic Review of the Literature

Diabetic retinopathy (DR) is a common microvascular complication of diabetes mellitus. The evidence connecting dietary intake and DR is emerging, but uncertain. We conducted a systematic review to comprehensively summarize the current understanding of the associations between dietary consumption, DR and diabetic macular edema (DME). We systematically searched PubMed, Embase, Medline, and the Cochrane Central Register of Controlled Trials between January 1967 to May 2022 for all studies investigating the effect of diet on DR and DME. Of the 4962 articles initially identified, 54 relevant articles were retained. Our review found that higher intakes of fruits, vegetables, dietary fibers, fish, a Mediterranean diet, oleic acid, and tea were found to have a protective effect against DR. Conversely, high intakes of diet soda, caloric intake, rice, and choline were associated with a higher risk of DR. No association was seen between vitamin C, riboflavin, vitamin D, and milk and DR. Only one study in our review assessed dietary intake and DME and found a risk of high sodium intake for DME progression. Therefore, the general recommendation for nutritional counseling to manage diabetes may be beneficial to prevent DR risk, but prospective studies in diverse diabetic populations are needed to confirm our findings and expand clinical guidelines for DR management.


Introduction
Diabetic retinopathy (DR; Figure 1) is a leading cause of vision loss globally. From 1990-2020, DR ranked as the fifth most common cause of preventable blindness and the fifth most common cause of moderate-to-worse visual impairment [1]. Approximately one in three people with diabetes mellitus suffer from DR and a third of these are afflicted with vision-threatening retinopathy, defined as severe non-proliferative DR or proliferative DR (PDR) or the presence of diabetic macular edema (DME) [2]. According to the Global Burden of Disease study, the age-standardized prevalence of blindness caused by DR showed a substantial increase between 1990 and 2020 in many regions of Asia [3], sub-Saharan Africa, as well as high-income North America [1]. The number of people with diabetes is estimated to be around 600 million by 2040 [4]. With this projected rise in the diabetic population coupled with increased life expectancy, the number of people with visual impairment due to DR is expected to rise worldwide [5]. Of concern is that DR is the most frequent cause of visual impairment among working-age individuals [1], and vision loss from DR places a considerable burden on patients' quality of life (QoL) [6]. Therefore, finding effective ways to prevent or control the progression of DR is of critical importance. Appropriate nutrition is an essential component of diabetes management [7]. Even though dietary guidelines for managing diabetes and prediabetes have been proposed [7], their role in the development and progression of DR has not been clearly defined. Nutrition counseling that works toward improving or controlling glycemic targets, attaining weight management goals, and enhancing cardiovascular risk factors (e.g., blood pressure, lipids, etc.) may benefit persons with DR. Studies show a favorable association between dietary changes and a reduction in the risk of DR [8,9]. Thus, adopting nutritional therapy in earlier stages may prevent the development and progression of DR and consequently help to reduce the treatment burden of this disease [10]. However, the risk factors for diabetes such as age, gender, and body mass index may not be necessarily risk factors for the development of DR. [11] Thus, the impact of diet modification on diabetes and that on DR may also differ.
Systematic reviews on the impact of diet on DR have been conducted [12][13][14][15][16]. Studies have recommended that the diet plays an important role in modifying the risk of DR by showing evidence of a protective effect of the Mediterranean diet, high fruit, vegetable, and fish intake, along with reduced calorie consumption, against the development of DR [12,13,15]. However, most of these dietary reviews on DR have focused on a specific food, nutrient, or dietary pattern [12][13][14]. Nevertheless, very few systematic reviews comprehensively assessed the entire spectrum of dietary components but are not very recent [15,16]. Several recent introductions of new dietary factors, i.e., selenium [17], vitamin B6 [18], vitamin B2 [17], choline [19], rice [20], cheese, wholemeal bread [21] and diet soda [22,23], with their influence on DR, are not included in previous comprehensive systematic reviews. For instance, two recent observational studies have highlighted diet soda as Appropriate nutrition is an essential component of diabetes management [7]. Even though dietary guidelines for managing diabetes and prediabetes have been proposed [7], their role in the development and progression of DR has not been clearly defined. Nutrition counseling that works toward improving or controlling glycemic targets, attaining weight management goals, and enhancing cardiovascular risk factors (e.g., blood pressure, lipids, etc.) may benefit persons with DR. Studies show a favorable association between dietary changes and a reduction in the risk of DR [8,9]. Thus, adopting nutritional therapy in earlier stages may prevent the development and progression of DR and consequently help to reduce the treatment burden of this disease [10]. However, the risk factors for diabetes such as age, gender, and body mass index may not be necessarily risk factors for the development of DR [11]. Thus, the impact of diet modification on diabetes and that on DR may also differ.
Systematic reviews on the impact of diet on DR have been conducted [12][13][14][15][16]. Studies have recommended that the diet plays an important role in modifying the risk of DR by showing evidence of a protective effect of the Mediterranean diet, high fruit, vegetable, and fish intake, along with reduced calorie consumption, against the development of DR [12,13,15]. However, most of these dietary reviews on DR have focused on a specific food, nutrient, or dietary pattern [12][13][14]. Nevertheless, very few systematic reviews comprehensively assessed the entire spectrum of dietary components but are not very recent [15,16]. Several recent introductions of new dietary factors, i.e., selenium [17], vitamin B6 [18], vitamin B2 [17], choline [19], rice [20], cheese, wholemeal bread [21] and diet soda [22,23], with their influence on DR, are not included in previous comprehensive systematic reviews. For instance, two recent observational studies have highlighted diet soda as a risk factor for DR [22,23]. Additionally, more studies sharing information on the effect of already known dietary factors on DR are also available, thus adding more valuable knowledge to the nutritional impact on DR. For example, newly added observational studies showing the protective effect of tea [24] and Mediterranean food [25] on DR support a similar finding in a previous systematic review [15]. In contrast, the protective effect of the consumption of coffee [26], shown by a new observational study, was not seen in the previous systematic review [16,27]. Lastly, DME is a vision-threatening manifestation of DR, more commonly seen in severe stages of DR [28], and the association between diet and DME has not been reported in previous reviews.
In the present systematic review, we wanted to comprehensively summarize the current understanding of the associations between dietary components, DR and diabetic macular edema (DME).

Literature Search
Using the PRISMA checklist (Supplementary Table S1 [29]; Figure 2), we conducted a systematic review of all studies published in peer-reviewed journals with no language restrictions. We retrieved articles from Embase, PubMed, Medline, and the Cochrane Central Register of Controlled Trials with a date range from January 1967 to May 2022. We systematically searched the database by combining the following keywords: diet OR dietary intake OR vitamins OR antioxidants OR nutrients OR fruits OR vegetables OR alcohol OR milk OR tea OR coffee OR carbohydrates OR fatty acid OR proteins AND diabetic retinopathy OR diabetic macular edema. a risk factor for DR [22,23]. Additionally, more studies sharing information on the effect of already known dietary factors on DR are also available, thus adding more valuable knowledge to the nutritional impact on DR. For example, newly added observational studies showing the protective effect of tea [24] and Mediterranean food [25] on DR support a similar finding in a previous systematic review [15]. In contrast, the protective effect of the consumption of coffee [26], shown by a new observational study, was not seen in the previous systematic review [16,27]. Lastly, DME is a vision-threatening manifestation of DR, more commonly seen in severe stages of DR [28], and the association between diet and DME has not been reported in previous reviews.
In the present systematic review, we wanted to comprehensively summarize the current understanding of the associations between dietary components, DR and diabetic macular edema (DME).

Literature Search
Using the PRISMA checklist (Supplementary Table S1 [29]; Figure 2), we conducted a systematic review of all studies published in peer-reviewed journals with no language restrictions. We retrieved articles from Embase, PubMed, Medline, and the Cochrane Central Register of Controlled Trials with a date range from January 1967 to May 2022. We systematically searched the database by combining the following keywords: diet OR dietary intake OR vitamins OR antioxidants OR nutrients OR fruits OR vegetables OR alcohol OR milk OR tea OR coffee OR carbohydrates OR fatty acid OR proteins AND diabetic retinopathy OR diabetic macular edema.

Study Selection
Our search methodology identified 5367 titles that were screened by ZY and systematically excluded if they did not meet predefined inclusion criteria. The exclusion was performed independently by ZY and vetted by JS, and uncertainty was clarified by JC. The reference list of those articles fulfilling the eligibility criteria was also verified for further relevant studies.

Inclusion Criteria
According to the PRISMA guidelines, a PICOS (participants, intervention, comparability, outcomes, study design) framework was used to formulate the eligibility criteria.

1.
Participants-Studies including human subjects with type1, type 2 diabetic mellitus, or both.

3.
Interventions or exposure-Studies that evaluated dietary intake using tools such as validated food frequency questionnaires, 24 h dietary recall, dietary history, or general interviewer-administered questionnaires. Dietary intake components included specific food, beverages, micronutrients, macronutrients, and dietary patterns ( Figure 3).

4.
Outcomes-It included prevalence, incidence, or progression of DR with or without DME. Studies that assessed DR outcomes by fundus photography, fundus examination using a direct or indirect ophthalmoscope, and fundus fluorescein angiography were accepted. Different scales for grading the severity of DR such as the Early Treatment Diabetic Retinopathy Study (ETDRS) and the International Classification system of DR were also accepted. The ETDRS is based on seven field stereophotographs, classifying DR from level 10 (absence of retinopathy) to level 85 (vitreous hemorrhage or retinal detachment involving macula). Conversely, the International Classification System grade cases into the categories of: no apparent retinopathy, mild, moderate, and severe non-proliferative retinopathy and final-stage proliferative diabetic retinopathy [30].

Study Selection
Our search methodology identified 5367 titles that were screened by ZY and systematically excluded if they did not meet predefined inclusion criteria. The exclusion was performed independently by ZY and vetted by JS, and uncertainty was clarified by JC. The reference list of those articles fulfilling the eligibility criteria was also verified for further relevant studies.

Inclusion Criteria
According to the PRISMA guidelines, a PICOS (participants, intervention, comparability, outcomes, study design) framework was used to formulate the eligibility criteria.    Studies that included the non-diabetic, pre-diabetic, or impaired glucose intolerance participants, or patients with special types of diabetes such as gestational diabetes.

3.
Studies with insufficient data, such as lack of exposure/outcome definitions or absence of statistical analysis which did not enable us to make conclusions.

4.
Studies that measured only biomarkers in serum, blood, or urine with no relation to dietary intake.

5.
Studies including intake in the form of supplements containing multiple different types of nutrients. 6.
Studies describing outcomes using abnormal retinal changes, microvascular complications, or visual acuity but not defined in the form of DR severity.

Data Extraction
Data on the name of the first author, year, type of study, sample size, diabetes type, and participant's age were extracted for each included study. Data extraction also included the components of dietary intake, method of assessment of dietary intake, DR outcome, DR diagnosis and its classification, confounders adjustment, statistical analysis, and summary of key findings. The ZY author performed the data extraction which was vetted by the JS author, and the JC author clarified uncertainty.

Study Quality Evaluation
The modified version of the Newcastle-Ottawa Scale (NOS; Figure 4) was used to evaluate the quality of observational studies [31]. In brief, the NOS is a scoring system whereby a maximum of 9 stars can be awarded to each study based upon three main criteria [32]:

3.
Exposure (for prospective or cross-sectional designs) or outcome (for case-control designs) (maximum of 3 stars).
Studies were awarded an additional star if they incorporated validated methods to assess dietary intake like validated food frequency questionnaires (FFQs), 24 h dietary recalls, 3-day food records, or serum biomarker levels. Studies were categorized as low in quality when awarded <4 stars, medium for 5-7 stars, and high for >8 stars.
We applied the Cochrane Collaboration Risk of Bias tool to assess the bias risk in interventional studies, i.e., randomized controlled trials. Briefly, a study was considered to have an overall low risk of bias when all key criteria were graded as having low bias risk; overall medium bias risk when all key criteria were graded to have low or unclear bias risk; and overall high bias risk when one or more key criteria were graded to have a high bias risk [33].

Description of Studies
We selected 54 papers from 4962 screened titles that met the requirements of our inclusion. (Figure 2). It included 3 interventional, 17 prospective, 29 cross-sectional, and 5 case-control studies.

Methodological Quality
Of 51 observational studies, the majority had high NOS scores, with 37 classified as "high quality" (≥8 stars) and 14 classified as "moderate quality" (5-7 stars). Of the 3 interventional studies, 2 and 1 had a high risk and medium risk of bias, respectively (Table 1).

Carotenoids
Tanaka and associates conducted a prospective study, finding that carotenoid intake was associated with reduced incident DR using a multivariate cox regression analysis of (Q4 [8.4 mg/day] intake vs. Q1 [2.6 mg/day] intake, hazard ratio [HR]: 0.52, 95% confidence interval [CI]: 0.33-0.81, p < 0.01) [48]. Using a cross-sectional study design, Shalini and associates also found a beneficial effect of carotene in DR [36]. They found that the plasma concentration of both pro-vitamin A (PVA) carotenoids (α-carotene, β-carotene, γ-carotene, α-cryptoxanthin, and β-cryptoxanthin) and non-PVA carotenoids (lutein, zeaxanthin, and lycopene) was significantly lower in the DR group compared to no DR patients and healthy controls (p < 0.001) [36]. Similarly, Zhang and associates also showed that higher dietary intake of retinol (100 µg/day) in type 2 diabetes patients was associated with a lower risk of DR (odds ratio [OR]: 0.88, 95%CI: 0.79-0.98, p = 0.025) [38]. However, the remaining three cross-sectional studies did not find significant associations between carotenoids and DR [35,44,46].   [48]. The work of Tanaka et al. was the only prospective study carried out on this topic. On the contrary, a cross-sectional study by Mayer-Davis and colleagues found an increased risk for more severe DR when vitamin C intake increased from the first quintile of intake to a higher level of intake. This result, however, is significant only for the ninth decile (OR = 2.21, p = 0.011) [35]. Prospective cohort studies measure events in chronological order and can be used to distinguish between cause and effect, whereas cross-sectional studies measure parameters at a single timepoint and do not permit distinction between cause and effect. Few other studies, however, suggest no association between vitamin C intake and DR before and/or after adjustment [17,46,50].

Vitamin E
The association between Vitamin E and DR remains uncertain. She and colleagues observed Vitamin E protective effects on DR (OR: 0.97, 95%CI: 0.95-1.00, p = 0.036) in their cross-sectional study after adjusting confounding factors [17]. Similarly, Granado-Casas showed a protective effect of Vitamin E on DR (OR: 0.85, 95%CI: 0.77-0.95, p = 0.006) [40]. Contrastingly, in a cross-sectional investigation by Mayer-Davis and colleagues, an increased intake of Vitamin E was associated with increased severity of DR among those not taking insulin (10th decile vs. 1st quintile, OR: 3.79, p < 0.02) [35]. The remaining one prospective and two cross-sectional studies did not report any significant association between Vitamin E and DR [46,48,50].

Selenium
A cross-sectional study conducted on the Chinese urban population by She and associates found selenium to have a protective effect against DR (OR: 0.98, 95%CI: 0.96-1.00, p = 0.017) [17].

Riboflavin
One cross-sectional study by She and associates found no significant difference between dietary intake of riboflavin in the DR group compared to the DR group (p = 0.129) [17].

Vitamin D
Neither a prospective nor a case-control study found any significant association between dietary vitamin D intake and DR [43,45].

Choline
A cross-sectional study by Liu and associates found that a higher dietary choline intake is associated with increased odds of DR in women compared with the lowest intake group (OR: 2.14, 95%CI: 1.38-3.31; p = 0.001) when using multivariable logistic regression models. However, this association was not statistically significant in men [19].

Calcium
A case-control study by Alcubierre on the Spanish population found no significant association between dietary calcium intake and DR [45]. Still, their study had a small sample size (n = 283), and no adjustment of confounders was performed [45]. However, Chen and associates found a protective effect of increased dietary intake of calcium from the risk of DR (OR: 0.70, 95%CI: 0.54-0.90, p = 0.005) in their cross-sectional study on the Chinese cohort and adjusted for multiple confounders such as serum glucose, hemoglobin, and smoking status [34].

Potassium
Chen and associates showed that increased dietary potassium intake was associated with reduced occurrence of DR (OR: 0.76, 95%CI: 0.59-0.97, p = 0.029) in their cross-sectional study [34], whereas Tanaka and colleagues did not find any significant association between potassium intake and the risk of DR in their prospective study [48].

Sodium
The findings of a prospective study by Horikawa and associates indicated that, among patients who consumed less than an average of 268.7 g of vegetables, high sodium intake was associated with a higher incidence of DR in elderly patients with type 2 diabetes ( [37]. Another prospective study by Roy and colleagues reported increased sodium intake as a risk factor for DME progression (Q4 vs. Q1, OR: 1.43, 95%CI: 1.10-1.86, p = 0.008), but there was no significant association with DR [49]. The evidence provided by the remaining studies showed no association of sodium intake with DR [47,53,54].

Monounsaturated Fatty Acids (MUFA)
A total of six studies evaluated the association between MUFA and DR. Out of these six studies, two were prospective studies, three were cross-sectional studies, and one was a case-control study (Table 3). Alcubierre and associates, who conducted a casecontrol study, reported that increased MUFA intake decreased DR prevalence (high MUFA intake [≥46.3 g] vs. low MUFA intake [≤36.0], OR: 0.42, 95%CI: 0.18-0.97, p = 0.034) [42]. The cross-sectional study performed by Granado-Casas and associates also showed that intake of MUFA was associated with a lower frequency of DR (OR: 0.95, 95%CI: 0.92-0.99], p = 0.012) [40]. In contrast, Cundiff and associates showed an opposite relationship between MUFA intake and DR progression in their prospective study, but confounders such as HbA1c, duration of diabetes, or diabetes treatment were not adjusted [53]. The remaining studies found no significant relationships between MUFA intake and DR [46,49,52].
Oleic acid is a specific type of MUFA, and its influence on DR was evaluated by a total of three studies (one cross-sectional, one case-control, and one prospective study). A case-control study by Alcubierre and co-workers showed a protective effect of oleic acid from DR (highest intake [≥43.6] vs. lowest intake [≤32.2] OR: 0.37, 95%CI: 0.16-0.85, p = 0.017) [42]. A cross-sectional study by Granado-Casas and co-workers also reported a similar finding [40]. However, Roy and colleagues did not find any significant relationship between oleic acid and DR in their prospective study [49].

Polyunsaturated Fatty Acids (PUFA)
Sala-Vila and associates found that middle and older age type 2 diabetic patients strictly adhering to dietary long-chain omega-3 PUFA (LCω3PUFA) recommendation of at least 500 mg/day was associated with a decreased risk of sight-threatening DR compared to those not fulfilling this recommendation (HR: 0.52, 95%CI: 0.31-0.88, p = 0.001) [12]. A crosssectional study performed by Sasaki and colleagues found that among well-controlled diabetic patients, increased daily consumption of PUFAs was associated with a reduced likelihood of  [46]. In contrast, Cundiff and colleagues showed an increase in DR progression with a higher intake of PUFA, but adjustment for confounders were not performed [53]. The remaining three studies did not show significant relationships between PUFA intake and DR [42,49,52] (Table 3).
There are two interventional studies with contrasting results. One survey by Houtsmuller and associates found that subjects who consumed a diet of unsaturated fat, rich in linoleic acid, had a significant reduction in DR progression compared to those on a saturated fat diet (p < 0.01) [55]. However, Howard-Williams and colleagues assessed that participants compliant with a modified fat diet (high PUFA-to-saturated fat ratio) tended to have a lower incidence of DR than those on a low-carbohydrate diet (low PUFA-to-saturated fat ratio) [56]. Still, this difference was not statistically significant [56].

Carbohydrates
A cross-sectional study by Granado-Casas, using adjusted multivariate analysis, showed that intake of complex carbohydrates was positively related to the presence of DR (OR: 1.02; 95%CI: 1.00-1.04, p = 0.031) [40]. On the other hand, two studies (one crosssectional, one prospective) showed an inverse association between carbohydrate intake and DR progression, but neither study adjusted for confounders [52,53]. The other four studies using a multivariable-adjusted model found no significant association between carbohydrate intake and DR [41,42,46,49] (Table 3).

Proteins
A prospective study by Park and colleagues found that the intake of glutamic acid and aspartic acid did not affect DR incidence [51]. Still, lower intake of aspartic acid showed an increased proliferative DR incidence, and the result remained consistent after adjustment (intake of aspartic acid in the highest tertile vs. lowest tertile for PDR, HR: 0.39, 95%CI: 0.16-0.96, p = 0.013) [51]. Another prospective study by Cundiff and colleagues showed that increased intake of proteins lowered progression of DR risk. Still, in their cross-sectional study, Roy and associates showed a risk relationship between protein intake and DR prevalence [52,53]. However, relevant confounders were not adjusted by these two studies. The remaining three studies, which adjusted for confounders, showed that dietary protein intake was not significantly associated with DR [42,46,49] (Table 3).  [48]. For dietary fiber, one prospective and two cross-sectional studies reported a protective effect on DR [52,53,57]. However, three studies (two prospective and one case-control study) reported no significant associations [21,42,49] (Table 4).

Cheese and Wholemeal Bread
Consumption of cheese and wholemeal bread showed a reduction in the risk of DR progression among the working-aged Australian diabetic population (cheese intake highest quartiles vs. lowest HR: 0.58, 95%CI: 0.41-0.83, p = 0.007 and wholemeal bread HR: 0.64, 95%CI: 0.46-0.89, p = 0.04) in a prospective study conducted by Yan and colleagues [21] (Table 4).

Fish oil
A prospective study by Sala-Vila and associates reported that consumption of two or more weekly servings of oily fish reduced the incidence of DR risk compared to those who did not consume this (HR: 0.41, 95%CI: 0.23-0.72, p < 0.002) [12]. In contrast, the association between fish oil intake and DR was found not to be significant by one prospective study [58] (Table 4).

Other Types of Food
No association was seen between consumption of processed meat, breakfast cereal, and seafood and DR progression in a prospective study by Yan and colleagues [21] (Table 4).

Coffee
A cross-sectional study by Lee and associates showed that the consumption of ≥2 cups of coffee per day reduced the prevalence of DR (OR: 0.53, 95%CI: 0.28-0.99, p for trend = 0.025) and vision-threatening DR (OR: 0.30, 95%CI: 0.10-0.91, p for trend = 0.005) in the Korean diabetics less than 65 years of age [26]. However, in their cross-sectional study, Kumari and associates found no significant association between coffee and DR [59] (Table 5).

Tea
Xu and associates found that long-term tea consumption (≥20 years) in elderly diabetic Chinese residents was a protective factor for DR compared to non-tea consumers (OR: 0:29, 95%CI: 0.09-0.97, p = 0.04) in their cross-sectional study [24]. Similarly, a case-control study on the Chinese diabetic population by Ma and associates reported a protective relationship between green tea intake and DR prevalence (intake vs. no intake, OR: 0.48, 95%CI: 0.24-0.97, p = 0.04) [60] (Table 5).

Milk
No association was observed between milk and DR progression in a prospective study by Yan and colleagues [21] (Table 5).

Diet Soda
Mirghani and colleagues, using a cross-sectional study design, found that diet soda (sugar-free carbonated beverage) consumption was associated with a higher risk of DR (p = 0.043) [22]. Another cross-sectional study by Fenwick and associates also found a positive association of diet drink (>4 cans [1.5 L]/week) consumption with proliferative DR (OR: 2.62, 95%CI: 1.14-6.06, p = 0.024) [23]. Still, no association was found between regular soft drinks and DR [23] (Table 5).

Alcohol
A prospective study on Indians living in Singapore by Gupta and associates found that alcohol consumption was associated with a reduction in incident DR compared to non-drinkers (OR: 0.36, 95%CI: 0.13-0.98, p = 0.045). Among alcohol consumers, occasional drinkers (≤2 days/week) had reduced occurrence of incident DR (OR: 0.17, 95%CI: 0.04-0.69, p = 0.013) compared with non-drinkers [61]. The other studies, which also reported protective effect of light-to-moderate alcohol consumption on the prevalence of DR, were cross-sectional studies [62][63][64][65] (Table 5).

Total Caloric Intake
Two prospective studies by Cundiff (r = 0.07, p < 0.007) and Roy (OR:1.41, 95%CI: 1.15-1.92, p = 0.002) reported a risk associated between a high total caloric intake and DR progression [49,53] whereas Alcubierre and associates found no significant association between high caloric intake and DR in their case-control study [42] (Table 5).

Discussion
From our systematic review on dietary intake and DR, we found that intake of fruits, vegetables and dietary fibers, fish, Mediterranean diet, oleic acid, and tea beverages had a protective effect on DR. We also found that selenium antioxidant, vitamin B6, cheese, and wholemeal bread may have a protective effect on DR. Still, this outcome was based on only one study in each of dietary component. The consumption of diet soda, increased caloric intake, rice, and choline was found to be associated with a greater risk of DR. In contrast, no significant association was found between vitamin C, riboflavin, and vitamin D and milk with DR. Other dietary components such as carotenoids, Vitamin E, potassium, unsaturated fatty acids, carbohydrates, coffee, and alcohol showed no clear relationship with DR, signifying that more studies are needed. The assessment of the influence of dietary intake on DME is limited to only one prospective study. This study found that a high intake of sodium was associated with DME progression. The findings from our systematic review may complement the current dietary recommendations for managing DR.

Protective Associations between Dietary Intake and Diabetic Retinopathy
In our review, high levels of consumption of fruits, vegetables, and dietary fibers has revealed strong protective effects against the development of DR [48,52,53,57]. Fruits and vegetables are rich sources of fiber and antioxidant compounds [74]. Dietary fiber delays glucose absorption from the intestines, thus reducing postprandial plasma glucose levels [75]. It also reduces inflammation and oxidative stress, which are known to be involved in the initiation and progression of diabetes [74]. Thus, dietary fiber would reduce the risk of hyperglycemia and oxidative stress-induced DR [76]. Fish oil is a rich source of long-chain omega-3 polyunsaturated fatty acid (LCω3PUFAs), which reduces the risk of diabetes [77] and is found to have a protective effect on DR in our review [12,20,39]. The retina is rich in LCω3PUFAs, particularly docosahexaenoic acid (DHA), which has antiinflammatory and anti-angiogenic properties [78,79] and experimental studies have shown the protective role of supplemental DHA or LCω3PUFAs against DR or neovascularization of the retina [80,81].
The Mediterranean diet is a centuries-old eating pattern consisting of plant-based foods such as fruits, vegetables, legumes, nuts, and whole grains. It also includes fish and olive oil and a low intake of red meat, red wine, and saturated fatty acids [82]. Our findings show the protective effect of the Mediterranean diet on DR. The anti-inflammatory and antioxidant compounds in the Mediterranean diet indirectly improve the peripheral uptake of glucose and reduce peripheral insulin resistance, and are thus proposed to have a protective effect in preventing diabetic microvascular complications [83]. Similarly, the protective role of Oleic acid against DR seen in our review is also proposed to improve peripheral insulin sensitivity. The two observational studies in the Chinese cohort in our review have shown the protective effect of tea on DR. However, results must be interpreted with caution, as these studies did not take other dietary factors such as fruits and vegetables into account [24,60]. Tea is one of the most consumed beverages in the world, and tea extracts are reported to have antioxidants and neuroprotective properties, improving insulin sensitivity, inhibiting ocular neovascularization and vascular permeability [84,85].

Adverse Associations between Dietary Intake and Diabetic Retinopathy
Two cross-sectional studies found diet soda to be a risk factor in the progression of DR. The proposed mechanism is an alteration of gut microbiota leading to inflammation, oxidative stress, and cardiometabolic states such as obesity, insulin resistance, and diabetes [86]. Another proposed theory is that the overconsumption of other food or beverages might occur due to subjects overestimating the calories saved by substituting diet beverages for sugar-sweetened drinks [23]. However, further longitudinal studies are required due to a small sample size of 200 participants [22], as well as a lack of an account of changes in diet drink, i.e. from regular soft drink to diet soft drink for lifestyle modification upon diagnosis of diabetes, which could overestimate the relationship between diet soda and DR in the study [23].
A prospective study in our review showed that increased rice consumption, which increased the total caloric intake, contributed to the increased risk of DR occurrence. A systematic review by Wong and associates found that high caloric intake increases the risk of DR [15,49,53]. Experimental and clinical evidence suggests that high caloric intake increases oxidative stress in diabetic patients, thus possibly increasing the risk of DR [87][88][89]. Interestingly, in our review, carbohydrates, one of the main contributors to total caloric intake, have shown no significant association with DR. Still, one cross-sectional study has shown a positive association with DR [40]. Despite a lack of substantial relationship with DR, it is crucial to monitor carbohydrate consumption to control postprandial hyperglycemia in patients with diabetes [90]. Thus, encouraging low-glycemic index and low-calorie meal intake may be favorable to prevent the occurrence and progression of diabetic microvascular complications [91,92]. The risk of choline causing increased DR risk for females needs further investigation by cross-sectional [19]. The literature has reported the adverse effect of choline and its metabolite, trimethylamine-N-oxide, by aggravating vascular endothelial cell dysfunction, oxidative stress, and inflammation, which are critical mechanisms of DR development [93,94].

No Significant Association between Dietary Intake and Diabetic Retinopathy
We did not find any significant association between antioxidants such as vitamin C, E, riboflavin, carotenoid intake and DR. This similar finding was also reported by Lee and associates [95]. However, in investigational studies, antioxidant supplementations inhibit oxidative stress and the development of DR [96,97]. Similarly, experimental studies have shown a beneficial effect of PUFA against the development of DR due to its anti-inflammatory and anti-angiogenic properties [81,98]. Still, the current review shows an inconclusive association. The studies in our review showing the associations of alcohol intake with DR risk have demonstrated contradictory results. Thus, our review could not confirm the protective effect of alcohol against DR, which supports the meta-analysis by Zhu and associates [99]. A moderate amount of alcohol consumption has demonstrated a beneficial effect on DR due to the high content of polyphenol, an antioxidant compound that inhibits angiogenesis, prevents inflammation, and facilitates vasorelaxation, all of which results in increased blood flow in the retina [100]. It also lowers plasma glucose levels by improving insulin sensitivity [101]. Such protective associations have been reported in a cross-sectional study and recently in a prospective study, but further longitudinal studies are required to confirm the protective association. The effect of common beverages such as milk and coffee are limited, with only one and two studies, respectively [21,26,59]. The routine diet is significantly composed of the above-listed dietary factors; thus, there is a need for large-scale longitudinal studies to understand their influence on the incidence and progression of DR.
The existing guidelines from the American Diabetic Association's (ADA) 2022 Diabetes Standard of Care support our findings, such as the benefits of the Mediterranean diet and the consumption of fruits, vegetables, and dietary fiber in cases of diabetes [102]. The ADA also recommends an increased intake of fish containing omega-3 fatty acids, which are also seen to be effective in DR prevention in our review. The evidence regarding the benefits of antioxidant supplements is insufficient in both the research of the ADA and our review. The ADA recommends limited sodium and carbohydrate consumption; however, we found no conclusive evidence to suggest detrimental effects of increased sodium and carbohydrate. Likewise, ADA recommends PUFAs and MUFAs intake as a replacement for saturated fat. It supports modest alcohol consumption, but our study results remain inconclusive regarding the effect of MUFA / PUFA and average alcohol intake on DR [102]. The findings from our review study are intended to complement and be considered simultaneously with the existing dietary guidelines in the overall management of diabetes.

Strengths and Limitations
The systematic review has several strengths as a method. Firstly, most studies in our review had good methodological and study qualities. Secondly, only dietary intake exposure and DRs outcome within human subjects were evaluated, excluding experimental animal and biomarker studies. This allowed us to translate results into nutritional recommendations for patients. Thirdly, studies conducted on diverse populations were included, thus providing more generalized results. However, our study also has some limitations, which may cause inconclusive outcomes between dietary intake and DR. First, FFQs were mostly used in dietary assessment and were administered only once, at the study baseline. Its major limitation is inaccurate assessment due to recall bias and subjectivity across individuals. Thus, combining methods such as the FFQ with dietary records (or 24 h dietary recall) or the FFQ with biomarker levels would provide more accurate estimates of nutritional intakes than a single assessment [103]. Second, most studies were cross-sectional, limiting the establishment of a causal association of dietary factors with DR; thus, there is a need for more longitudinal studies. Third, most studies have evaluated a single dietary component or nutrient rather than a dietary pattern that examines the effects of the overall diet. Instead of focusing on a single nutrient, broader dietary patterns, including beverages, would reflect real-world food consumption habits, which would be more predictive of disease risk and help to translate into more precise dietary guidelines [104]. Fourth, only one study evaluated the influence of dietary intake on DME; thus, there is a need for future studies in order to establish a better knowledge of the mechanisms of diet on DME, which may differ from DR. Fifth, many studies did not differentiate the effect of dietary intake on type 1 and type 2 diabetes or other types of diabetes such as gestational or autoimmune which is needed as etiology, pathophysiology, epidemiology, and disease management are not similar in a different type of diabetes. Lastly, methods assessing dietary intake exposure and DR outcomes are heterogeneous, thus affecting comparability. For example, the number of DR cases in studies examined by two-field or non-mydriatic fundus photographs may be underestimated compared to studies that used stereoscopic 7-field fundus photographs (the standard reference for DR detection as defined by the ETDRS) [105]. Therefore, further studies should be conducted on all different types of diabetes.

Conclusions
DR affects one-third of individuals with diabetes, and multiple studies depict the association between dietary intake and diabetic eye changes. While we do not fully understand the underlying mechanism that results in or worsens DR and/or DME in people with various dietary intakes, they are likely to influence glycemic management and cardiovascular risk factors. Nonetheless, diabetic patients at risk of developing DR may benefit from nutritional recommendations, as elucidated by the studies described.