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State-of-the-Art Research on Diabetic Retinopathy
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State-of-the-Art Research on Diabetic Retinopathy

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Ophthalmology".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 38202

Special Issue Editor

Prof. Dr. Rafael Simó

E-Mail Website
Guest Editor
1. Vall d'Hebron Research Institute (VHIR), Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain
2. CIBER de Diabetes i Enfermedades Metabólicas Asociadas (ISCIII), 28220 Madrid, Spain
3. Derpartment of Medicine-Endocrinology, Autonomous Univeristy of Barcelona, 08035 Bacelona, Spain
Interests: diabetes mellitus; complications of diabetes; diabetes microangiopathy; diabetic retinopathy; neurodegeneration; clinical diabetes; personalized treatment of diabetes
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Diabetic retinopathy (DR) is a common complication of diabetes and remains a leading cause of severe loss of visual acuity and blindness, thus representing a significant economic burden for the health-care systems. Experimental research has notably evolved in recent years and the classic definition of DR as a merely microangiopathic complication of diabetes has been replaced by a more integrative term, such as a “highly-specific neurovascular disease.” This Special Issue aims to show the main current topics in basic, translational, and clinical research, as well as to examine the scientific gaps and other limiting factors that impede advances in this field. A special emphasis will be aimed at new pharmacologic strategies based on targeting the underlying mechanisms. In addition, the clinical meaning of diabetic retinopathy as a risk factor of either classic (i.e., cardiovascular disease) or emergent (i.e., cognitive impairment) complications will be examined.

We trust that your participation in this Special Issue devoted to the current research on diabetic retinopathy will contribute to the improvement not only of our understanding on its pathophysiology and relation to other diabetic complications, but will also allow us to design more efficient therapeutic strategies.

Dr. Rafael Simó
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Diabetic retinopathy
  • Research in diabetic retinopathy
  • Microangiopathy
  • Neurovascular unit
  • Neurodegeneration
  • Clinical aspects of diabetic retinopathy
  • Treatment of diabetic retinopathy

Published Papers (16 papers)

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Editorial

Jump to: Research, Review

3 pages, 206 KiB  
Editorial
State-of-the-Art Research on Diabetic Retinopathy
by Rafael Simó
J. Clin. Med. 2022, 11(13), 3790; https://doi.org/10.3390/jcm11133790 - 30 Jun 2022
Viewed by 1079
Abstract
The scientific community and health care providers should be seriously worried by the fact that diabetic retinopathy (DR) remains the main cause of preventable blindness in the working age population [...] Full article
(This article belongs to the Special Issue State-of-the-Art Research on Diabetic Retinopathy)

Research

Jump to: Editorial, Review

11 pages, 1183 KiB  
Article
Retinal Microvascular and Neuronal Changes Are Also Present, Even If Differently, in Adolescents with Type 1 Diabetes without Clinical Diabetic Retinopathy
by Elisabetta Pilotto, Tommaso Torresin, Francesca Leonardi, Joaquin Gutierrez De Rubalcava Doblas, Giulia Midena, Carlo Moretti and Edoardo Midena
J. Clin. Med. 2022, 11(14), 3982; https://doi.org/10.3390/jcm11143982 - 8 Jul 2022
Cited by 6 | Viewed by 1355
Abstract
The purpose of this study was to evaluate retinal changes in adolescents with childhood-onset, long-lasting type 1 diabetes mellitus (T1D). Patients and healthy controls (HC) underwent optical coherence tomography (OCT) and OCT-angiography (OCTA). Individual macular layers, peripapillary retinal nerve fiber layer (pRNFL), and [...] Read more.
The purpose of this study was to evaluate retinal changes in adolescents with childhood-onset, long-lasting type 1 diabetes mellitus (T1D). Patients and healthy controls (HC) underwent optical coherence tomography (OCT) and OCT-angiography (OCTA). Individual macular layers, peripapillary retinal nerve fiber layer (pRNFL), and vascular parameters (vessel area density (VAD), vessel length fraction (VLF) and vessel diameter index (VDI)) of macular superficial vascular (SVP), intermediate (ICP), deep (DCP) and radial peripapillary capillary plexuses (RPCP) were quantified. Thirty-nine patients (5 with (DR group) and 34 without (noDR group) diabetic retinopathy) and 20 HC were enrolled. The pRNFL and ganglion cell layer (GCL) were thicker in noDR compared to HC and DR, reaching statistically significant values versus HC for some sectors. At the macular level, VAD and VLF were reduced in DR versus HC in all plexuses, and versus noDR in SVP (p < 0.005 for all). At the RPCP level, VAD and VDI were increased in noDR versus HC, significantly for VDI (p = 0.0067). Glycemic indices correlated to retinal parameters. In conclusion, in T1D adolescents, retinal capillary and neuronal changes are present after long-lasting disease, even in the absence of clinical DR. These changes modify when clinical retinopathy develops. The precocious identification of specific OCT and OCTA changes may be a hallmark of subsequent overt retinopathy. Full article
(This article belongs to the Special Issue State-of-the-Art Research on Diabetic Retinopathy)
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15 pages, 2526 KiB  
Article
Optical Coherence Tomography Angiography in Type 1 Diabetes Mellitus—Report 2: Diabetic Kidney Disease
by Aníbal Alé-Chilet, Carolina Bernal-Morales, Marina Barraso, Teresa Hernández, Cristian Oliva, Irene Vinagre, Emilio Ortega, Marc Figueras-Roca, Anna Sala-Puigdollers, Cristina Esquinas, Marga Gimenez, Enric Esmatjes, Alfredo Adán and Javier Zarranz-Ventura
J. Clin. Med. 2022, 11(1), 197; https://doi.org/10.3390/jcm11010197 - 30 Dec 2021
Cited by 7 | Viewed by 1735
Abstract
The purpose of this study is to investigate potential associations between optical coherence tomography angiography (OCTA) parameters and diabetic kidney disease (DKD) categories in type 1 diabetes mellitus (T1DM) patients and controls. A complete ocular and systemic examination, including OCTA imaging tests and [...] Read more.
The purpose of this study is to investigate potential associations between optical coherence tomography angiography (OCTA) parameters and diabetic kidney disease (DKD) categories in type 1 diabetes mellitus (T1DM) patients and controls. A complete ocular and systemic examination, including OCTA imaging tests and bloods, was performed. OCTA parameters included vessel density (VD), perfusion density (PD), foveal avascular zone area (FAZa), perimeter (FAZp) and circularity (FAZc) in the superficial vascular plexus, and DKD categories were defined according to glomerular filtration rate (GFR), albumin-creatinine ratio (ACR) and KDIGO prognosis risk classifications. A total of 425 individuals (1 eye/1 patient) were included. Reduced VD and FAZc were associated with greater categories of GFR (p = 0.002, p = 0.04), ACR (p = 0.003, p = 0.005) and KDIGO risk prognosis classifications (p = 0.002, p = 0.005). FAZc was significantly reduced in greater KDIGO prognosis risk categories (low risk vs. moderate risk, 0.65 ± 0.09 vs. 0.60 ± 0.07, p < 0.05). VD and FAZc presented the best diagnostic performance in ROCs. In conclusion, OCTA parameters, such as VD and FAZc, are able to detect different GFR, ACR, and KDIGO categories in T1DM patients and controls in a non-invasive, objective quantitative way. FAZc is able to discriminate within T1DM patients those with greater DKD categories and greater risk of DKD progression. Full article
(This article belongs to the Special Issue State-of-the-Art Research on Diabetic Retinopathy)
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18 pages, 2799 KiB  
Article
GSH-Independent Induction of ER Stress during Hypoglycaemia in the Retinal Cells of Mice
by Daria Fresia, Enrica Cannizzaro, Angelica Borgo and Raphaël Roduit
J. Clin. Med. 2021, 10(11), 2529; https://doi.org/10.3390/jcm10112529 - 7 Jun 2021
Cited by 4 | Viewed by 2587
Abstract
Glucose is one of the most important metabolic substrates of the retina, and glycaemic imbalances can lead to serious side effects, including retinopathy. We previously showed that hypoglycaemia induces retinal cell death in mice, as well as the implication of glutathione (GSH) in [...] Read more.
Glucose is one of the most important metabolic substrates of the retina, and glycaemic imbalances can lead to serious side effects, including retinopathy. We previously showed that hypoglycaemia induces retinal cell death in mice, as well as the implication of glutathione (GSH) in this process. This study aimed to analyse the role of low glucose-induced decrease in GSH levels in endoplasmic reticulum (ER) stress. We cultured 661W photoreceptor-like cells under various glucose conditions and analysed ER stress markers at the mRNA and protein levels. We used the ERAI (“ER stress-activated indicator”) mouse model to test ER stress in both ex vivo, on retinal explants, or in vivo, in mice subjected to hypoglycaemia. Moreover, we used buthionine sulfoximine (BSO) and glutamate cysteine ligase (Gclm)-KO mice as models of low GSH to test its effects on ER stress. We show that the unfolded protein response (UPR) is triggered in 661W cells and in ERAI mice under hypoglycaemic conditions. Low GSH levels promote cell death, but have no impact on ER stress. We concluded that low glucose levels induce ER stress independently of GSH levels. Inhibition of ER stress could prevent neurodegeneration, which seems to be an early event in the pathogenesis of diabetic retinopathy. Full article
(This article belongs to the Special Issue State-of-the-Art Research on Diabetic Retinopathy)
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16 pages, 1402 KiB  
Article
HspB4/αA-Crystallin Modulates Neuroinflammation in the Retina via the Stress-Specific Inflammatory Pathways
by Madhu Nath, Yang Shan, Angela M. Myers and Patrice Elie Fort
J. Clin. Med. 2021, 10(11), 2384; https://doi.org/10.3390/jcm10112384 - 28 May 2021
Cited by 11 | Viewed by 2532
Abstract
Purpose: We have previously demonstrated that HspB4/αA-crystallin, a molecular chaperone, plays an important intrinsic neuroprotective role during diabetes, by its phosphorylation on residue 148. We also reported that HspB4/αA-crystallin is highly expressed by glial cells. There is a growing interest in the potential [...] Read more.
Purpose: We have previously demonstrated that HspB4/αA-crystallin, a molecular chaperone, plays an important intrinsic neuroprotective role during diabetes, by its phosphorylation on residue 148. We also reported that HspB4/αA-crystallin is highly expressed by glial cells. There is a growing interest in the potential causative role of low-grade inflammation in diabetic retinopathy pathophysiology and retinal Müller glial cells’ (MGCs’) participation in the inflammatory response. MGCs indeed play a central role in retinal homeostasis via secreting various cytokines and other mediators. Hence, this study was carried out to delineate and understand the regulatory function of HspB4/αA-crystallin in the inflammatory response associated with metabolic stresses. Methods: Primary MGCs were isolated from knockout HspB4/αA-crystallin mice. These primary cells were then transfected with plasmids encoding either wild-type (WT), phosphomimetic (T148D), or non-phosphorylatable mutants (T148A) of HspB4/αA-crystallin. The cells were exposed to multiple metabolic stresses including serum starvation (SS) or high glucose with TNF-alpha (HG + T) before being further evaluated for the expression of inflammatory markers by qPCR. The total protein expression along with subcellular localization of NF-kB and the NLRP3 component was assessed by Western blot. Results: Elevated levels of IL-6, IL-1β, MCP-1, and IL-18 in SS were significantly diminished in MGCs overexpressing WT and further in T148D as compared to EV. The HG + T-induced increase in these inflammatory markers was also dampened by WT and even more significantly by T148D overexpression, whereas T148A was ineffective in either stress. Further analysis revealed that overexpression of WT or the T148D, also led to a significant reduction of Nlrp3, Asc, and caspase-1 transcript expression in serum-deprived MGCs and nearly abolished the NF-kB induction in HG + T diabetes-like stress. This mechanistic effect was further evaluated at the protein level and confirmed the stress-dependent regulation of NLRP3 and NF-kB by αA-crystallin. Conclusions: The data gathered in this study demonstrate the central regulatory role of HspB4/αA-crystallin and its modulation by phosphorylation on T148 in retinal MGCs. For the first time, this study demonstrates that HspB4/αA-crystallin can dampen the stress-induced expression of pro-inflammatory cytokines through the modulation of multiple key inflammatory pathways, therefore, suggesting its potential as a therapeutic target for the modulation of chronic neuroinflammation. Full article
(This article belongs to the Special Issue State-of-the-Art Research on Diabetic Retinopathy)
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13 pages, 570 KiB  
Article
Derivation and Validation of Essential Predictors and Risk Index for Early Detection of Diabetic Retinopathy Using Electronic Health Records
by Ru Wang, Zhuqi Miao, Tieming Liu, Mei Liu, Kristine Grdinovac, Xing Song, Ye Liang, Dursun Delen and William Paiva
J. Clin. Med. 2021, 10(7), 1473; https://doi.org/10.3390/jcm10071473 - 2 Apr 2021
Cited by 14 | Viewed by 2621
Abstract
Diabetic retinopathy (DR) is a leading cause for blindness among working-aged adults. The growing prevalence of diabetes urges for cost-effective tools to improve the compliance of eye examinations for early detection of DR. The objective of this research is to identify essential predictors [...] Read more.
Diabetic retinopathy (DR) is a leading cause for blindness among working-aged adults. The growing prevalence of diabetes urges for cost-effective tools to improve the compliance of eye examinations for early detection of DR. The objective of this research is to identify essential predictors and develop predictive technologies for DR using electronic health records. We conducted a retrospective analysis on a derivation cohort with 3749 DR and 94,127 non-DR diabetic patients. In the analysis, an ensemble predictor selection method was employed to find essential predictors among 26 variables in demographics, duration of diabetes, complications and laboratory results. A predictive model and a risk index were built based on the selected, essential predictors, and then validated using another independent validation cohort with 869 DR and 6448 non-DR diabetic patients. Out of the 26 variables, 10 were identified to be essential for predicting DR. The predictive model achieved a 0.85 AUC on the derivation cohort and a 0.77 AUC on the validation cohort. For the risk index, the AUCs were 0.81 and 0.73 on the derivation and validation cohorts, respectively. The predictive technologies can provide an early warning sign that motivates patients to comply with eye examinations for early screening and potential treatments. Full article
(This article belongs to the Special Issue State-of-the-Art Research on Diabetic Retinopathy)
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12 pages, 3247 KiB  
Article
Clinical Characteristics, Preventive Care and Attitude to Telemedicine among Patients with Diabetic Retinopathy: A Cross-Sectional Study
by Siddarth Agrawal, Bartłomiej Strzelec, Rafał Poręba, Anil Agrawal and Grzegorz Mazur
J. Clin. Med. 2021, 10(2), 249; https://doi.org/10.3390/jcm10020249 - 12 Jan 2021
Cited by 5 | Viewed by 1919
Abstract
Diabetic retinopathy (DR) is the most frequent and one of the most severe complications of both types of diabetes. Despite the development of versatile diabetes management programs in most developed countries, many patients remain at increased risk for developing this life-limiting and life-threatening [...] Read more.
Diabetic retinopathy (DR) is the most frequent and one of the most severe complications of both types of diabetes. Despite the development of versatile diabetes management programs in most developed countries, many patients remain at increased risk for developing this life-limiting and life-threatening condition. This cross-sectional analysis objective was to examine and compare the prevalence of diabetic retinopathy and comorbidities, as well as the clinical characteristics, prevention patterns, and attitude to telemedicine in patients with diabetes. We found that, when compared to the non-DR group, patients with DR significantly more often utilize clinical preventive services and counseling; however, there is still a significant gap in the receipt of preventative care. Moreover, in the DR subgroup, inadequate diabetic control and the presence of various signs and symptoms of diseases were observed. Although less than a fifth of all patients use mobile applications to monitor their health status, the patients indicate their willingness to use telemedical technology, particularly if it is recommended by the physician and provided without additional costs. The evolution of telemedicine offers a possibility of inexpensive, continuous monitoring of the disease that could improve treatment outcomes. Our observations emphasize DR’s perception as a complex disease in which education and continuous monitoring, particularly with telemedicine methods, are critical for further improvement in chronic care. Full article
(This article belongs to the Special Issue State-of-the-Art Research on Diabetic Retinopathy)
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15 pages, 2206 KiB  
Article
Fenofibrate Reduces the Severity of Neuroretinopathy in a Type 2 Model of Diabetes without Inducing Peroxisome Proliferator-Activated Receptor Alpha-Dependent Retinal Gene Expression
by Jennifer M. Enright, Sheng Zhang, Christina Thebeau, Emily Siebert, Alexander Jin, Veda Gadiraju, Xiaodong Zhang, Shiming Chen, Clay F. Semenkovich and Rithwick Rajagopal
J. Clin. Med. 2021, 10(1), 126; https://doi.org/10.3390/jcm10010126 - 31 Dec 2020
Cited by 13 | Viewed by 2614
Abstract
Fenofibrate slows the progression of clinical diabetic retinopathy (DR), but its mechanism of action in the retina remains unclear. Fenofibrate is a known agonist of peroxisome proliferator-activated receptor alpha (PPARα), a transcription factor critical for regulating metabolism, inflammation and oxidative stress. Using a [...] Read more.
Fenofibrate slows the progression of clinical diabetic retinopathy (DR), but its mechanism of action in the retina remains unclear. Fenofibrate is a known agonist of peroxisome proliferator-activated receptor alpha (PPARα), a transcription factor critical for regulating metabolism, inflammation and oxidative stress. Using a DR mouse model, db/db, we tested the hypothesis that fenofibrate slows early DR progression by activating PPARα in the retina. Relative to healthy littermates, six-month-old db/db mice exhibited elevated serum triglycerides and cholesterol, retinal gliosis, and electroretinography (ERG) changes including reduced b-wave amplitudes and delayed oscillatory potentials. These pathologic changes in the retina were improved by oral fenofibrate. However, fenofibrate did not induce PPARα target gene expression in whole retina or isolated Müller glia. The capacity of the retina to respond to PPARα was further tested by delivering the PPARα agonist GW590735 to the intraperitoneal or intravitreous space in mice carrying the peroxisome proliferator response element (PPRE)-luciferase reporter. We observed strong induction of the reporter in the liver, but no induction in the retina. In summary, fenofibrate treatment of db/db mice prevents the development of early DR but is not associated with induction of PPARα in the retina. Full article
(This article belongs to the Special Issue State-of-the-Art Research on Diabetic Retinopathy)
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11 pages, 1774 KiB  
Article
Quantitative Color Fundus Autofluorescence in Patients with Diabetes Mellitus
by Stela Vujosevic, Caterina Toma, Paolo Nucci, Marco Brambilla and Stefano De Cillà
J. Clin. Med. 2021, 10(1), 48; https://doi.org/10.3390/jcm10010048 - 25 Dec 2020
Cited by 5 | Viewed by 2386
Abstract
A new short wavelength confocal blue-light 450 nm-fundus autofluorescence (color-FAF) allows for visualization of minor fluorophores (e.g., advanced glycation end products, AGEs), besides lipofuscin. The aim of the present pilot study was to quantitatively evaluate color-FAF in patients with diabetes mellitus (DM) and [...] Read more.
A new short wavelength confocal blue-light 450 nm-fundus autofluorescence (color-FAF) allows for visualization of minor fluorophores (e.g., advanced glycation end products, AGEs), besides lipofuscin. The aim of the present pilot study was to quantitatively evaluate color-FAF in patients with diabetes mellitus (DM) and to correlate these data with different stages of retinal disease severity. Optical coherence tomography and color-FAF images of 193 patients/eyes and 18 controls were analyzed using a custom software for quantification of the long (red) and short (green) wavelength components of the emission spectrum (REFC/GEFC). Measurements were performed in nine quadrants of the 6-mm ETDRS macular grid. Foveal GEFC and REFC intensities were higher in patients with DM compared to controls (p = 0.015 and p = 0.006 respectively) and in eyes with center involving diabetic macular edema (DME) compared to eyes without DME (p < 0.001). A positive correlation was found between GEFC and REFC intensities and central retinal thickness, r = 0.37 (p < 0.001) and r = 0.42 (p < 0.001), respectively. No differences were found in color-FAF among different DR severity groups. Quantitative color-FAF could become helpful for the metabolic evaluation of retina in patients with DM and in DME; however, further histologic and immunohistochemical studies on distribution of different retinal fluorophores in DM are needed to better understand its role. Full article
(This article belongs to the Special Issue State-of-the-Art Research on Diabetic Retinopathy)
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11 pages, 2176 KiB  
Article
High-Glucose-Induced Rab20 Upregulation Disrupts Gap Junction Intercellular Communication and Promotes Apoptosis in Retinal Endothelial and Müller Cells: Implications for Diabetic Retinopathy
by Dongjoon Kim, Casey Stottrup Lewis, Vijay P. Sarthy and Sayon Roy
J. Clin. Med. 2020, 9(11), 3710; https://doi.org/10.3390/jcm9113710 - 19 Nov 2020
Cited by 10 | Viewed by 1940
Abstract
To investigate whether high glucose (HG) alters Rab20 expression and compromises gap junction intercellular communication (GJIC) and cell survival, retinal cells were studied for altered intracellular trafficking of connexin 43 (Cx43). Retinal endothelial cells (RRECs) and retinal Müller cells (rMCs) were grown in [...] Read more.
To investigate whether high glucose (HG) alters Rab20 expression and compromises gap junction intercellular communication (GJIC) and cell survival, retinal cells were studied for altered intracellular trafficking of connexin 43 (Cx43). Retinal endothelial cells (RRECs) and retinal Müller cells (rMCs) were grown in normal (N; 5 mM glucose) or HG (30 mM glucose) medium for seven days. In parallel, cells grown in HG medium were transfected with either Rab20 siRNA or scrambled siRNA as a control. Rab20 and Cx43 expression and their localization and distribution were assessed using Western Blot and immunostaining, respectively. Changes in GJIC activity were assessed using scrape load dye transfer, and apoptosis was identified using differential dye staining assay. In RRECs or rMCs grown in HG medium, Rab20 expression was significantly increased concomitant with a decreased number of Cx43 plaques. Importantly, a significant increase in the number of Cx43 plaques and GJIC activity was observed in cells transfected with Rab20 siRNA. Additionally, Rab20 downregulation inhibited HG-induced apoptosis in RRECs and rMCs. Results indicate HG-mediated Rab20 upregulation decreases Cx43 localization at the cell surface, resulting in compromised GJIC activity. Reducing Rab20 expression could be a useful strategy in preventing HG-induced vascular and Müller cell death associated with diabetic retinopathy. Full article
(This article belongs to the Special Issue State-of-the-Art Research on Diabetic Retinopathy)
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14 pages, 897 KiB  
Article
A Phase 2 Clinical Trial on the Use of Cibinetide for the Treatment of Diabetic Macular Edema
by Noemi Lois, Evie Gardner, Margaret McFarland, David Armstrong, Christine McNally, Nuala Jane Lavery, Christina Campbell, Rita I Kirk, Daiva Bajorunas, Ann Dunne, Anthony Cerami and Michael Brines
J. Clin. Med. 2020, 9(7), 2225; https://doi.org/10.3390/jcm9072225 - 14 Jul 2020
Cited by 7 | Viewed by 3546
Abstract
Purpose: Evaluating the effects of cibinetide in diabetic macular edema (DME). Methods: Phase 2 trial. Naïve patients with >400 µm central retinal thickness (CRT) DME in one/both eyes were recruited (May 2016–April 2017) at the Belfast Health and Social Care Trust. The study [...] Read more.
Purpose: Evaluating the effects of cibinetide in diabetic macular edema (DME). Methods: Phase 2 trial. Naïve patients with >400 µm central retinal thickness (CRT) DME in one/both eyes were recruited (May 2016–April 2017) at the Belfast Health and Social Care Trust. The study eye was that with best vision and lowest CRT. Patients self-administered cibinetide 4 mg/day subcutaneously for 12 weeks. Primary and secondary outcomes: mean change from baseline to week 12 in best corrected visual acuity (BCVA), CRT, central retinal sensitivity, tear production, patient-reported outcomes, adverse events and antibodies to cibinetide. Descriptive statistics were used; exploratory analyses focused on non-study eyes, diabetic control, serum cytokines and albuminuria. Results: Nine patients were recruited; eight completed the study. There was no improvement in mean change baseline-week 12 in BCVA (−2.9 + 5.0), CRT (10 + 94.6 microns), central retinal sensitivity (−0.53 + 1.9 dB) or tear production (−0.13 + 7.7 mm), but there was an improvement in National Eye Institute Visual Function Questionnaire (NEI VFQ-25) composite scores (2.7 + 3.1). Some participants experienced improvements in CRT, tear production, diabetic control and albuminuria. No serious adverse events/reactions or anti-cibinetide antibodies were seen. Conclusions: The cibinetide 12-week course was safe. Improvements in NEI VFQ-25 scores, CRT, tear production, diabetic control and albuminuria, observed in some participants, warrant further investigation. Trial Registration: EudraCT number: 2015-001940-12. ISRCTN16962255—registration date 25.06.15. Full article
(This article belongs to the Special Issue State-of-the-Art Research on Diabetic Retinopathy)
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12 pages, 1076 KiB  
Article
Utility of Insulin Resistance in Estimating Cardiovascular Risk in Subjects with Type 1 Diabetes According to the Scores of the Steno Type 1 Risk Engine
by Albert Cano, Gemma Llauradó, Lara Albert, Isabel Mazarico, Brenno Astiarraga, Montserrat González-Sastre, Laia Martínez, Sonia Fernández-Veledo, Rafael Simó, Joan Vendrell and José-Miguel González-Clemente
J. Clin. Med. 2020, 9(7), 2192; https://doi.org/10.3390/jcm9072192 - 11 Jul 2020
Cited by 9 | Viewed by 1894
Abstract
Background: We sought to assess the potential of insulin resistance (IR) for estimating cardiovascular disease (CVD) risk in adults with type 1 diabetes (T1DM) according to the scores of the Steno Type 1 Risk Engine (ST1RE). Methods: A total of 179 adults with [...] Read more.
Background: We sought to assess the potential of insulin resistance (IR) for estimating cardiovascular disease (CVD) risk in adults with type 1 diabetes (T1DM) according to the scores of the Steno Type 1 Risk Engine (ST1RE). Methods: A total of 179 adults with T1DM (50.8% men, age 41.2 ± 13.1 years, duration of T1DM 16 (12–23) years) without established CVD were evaluated. IR was assessed by the estimation of insulin sensitivity (eIS) using two validated prediction equations: the estimated insulin sensitivity developed from the Pittsburgh Epidemiology of Diabetes Complications Study (eIS-EDC) and the estimated insulin sensitivity developed from Coronary Artery Calcification in T1DM Study (eIS-CACTI) ST1RE was used to estimate 10-year CVD risk and to classify subjects into three groups according to their risk: low (<10%; n = 105), moderate (10–20%; n = 53), and high (≥20%; n = 21). Results: Both eIS-EDC and eIS-CACTI correlated negatively with ST1RE scores (eIS-EDC: r = −0.636, p < 0.001; eIS-CACTI: r = −0.291, p < 0.001). The C-statistic for predicting moderate/high risk and high risk was 0.816 (95% confidence interval (CI): 0.754–0.878) and 0.843 (95% CI: 0.772–0.913), respectively, for the eIS-EDC equation, and was 0.686 (95% CI: 0.609–0.763) and 0.646 (95% CI: 0.513–0.778), respectively, for the eIS-CACTI equation. The eIS-EDC equation had a significantly higher C-statistic both for moderate-/high-risk (p = 0.001) and high-risk (p = 0.007) subjects. Two cut-off points of eIS-EDC were identified for detecting moderate/high risk (8.52 mg·kg−1·min−1; sensitivity 74% and specificity 76%) and high risk (8.08 mg·kg−1·min−1; sensitivity 65% and specificity 95%) with potential applicability in clinical practice. Conclusions: eIS negatively correlates with the score of CVD risk in the ST1RE. Two cut-off points of eIS are reported with potential utility in clinical practice for detecting adults with T1DM with the highest CVD risk. Full article
(This article belongs to the Special Issue State-of-the-Art Research on Diabetic Retinopathy)
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Review

Jump to: Editorial, Research

11 pages, 1299 KiB  
Review
Ultrawide Field Imaging in Diabetic Retinopathy: Exploring the Role of Quantitative Metrics
by Mohamed Ashraf, Jerry D. Cavallerano, Jennifer K. Sun, Paolo S. Silva and Lloyd Paul Aiello
J. Clin. Med. 2021, 10(15), 3300; https://doi.org/10.3390/jcm10153300 - 27 Jul 2021
Cited by 8 | Viewed by 2633
Abstract
Ultrawide field imaging (UWF) has allowed the visualization of a significantly greater area of the retina than previous standard approaches. In diabetic retinopathy (DR), significantly more lesions are seen on UWF imaging compared to the seven-standard ETDRS fields. In addition, some eyes have [...] Read more.
Ultrawide field imaging (UWF) has allowed the visualization of a significantly greater area of the retina than previous standard approaches. In diabetic retinopathy (DR), significantly more lesions are seen on UWF imaging compared to the seven-standard ETDRS fields. In addition, some eyes have lesions that are located predominantly in the peripheral retina that are associated with an increased risk of DR progression. The current DR severity scales are still largely based on clinically visible retinal microvascular lesions and do not incorporate retinal periphery, neuroretinal, or pathophysiologic changes. Thus, current scales are not well suited for documenting progression or regression in eyes with very early or advanced DR, nor in the setting of vascular endothelial growth factor inhibitors (antiVEGF). In addition, the categorical system is highly subjective, and grading is variable between different graders based on experience level and training background. Recently, there have been efforts to quantify DR lesions on UWF imaging in an attempt to generate objective metrics for classification, disease prognostication and prediction of treatment response. The purpose of this review is to examine current quantitative metrics derived from UWF fluorescein angiograms and UWF color imaging to determine their feasibility in any potential future DR classification. Full article
(This article belongs to the Special Issue State-of-the-Art Research on Diabetic Retinopathy)
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10 pages, 272 KiB  
Review
Subthreshold Micropulse Laser Modulates Retinal Neuroinflammatory Biomarkers in Diabetic Macular Edema
by Luisa Frizziero, Andrea Calciati, Giulia Midena, Tommaso Torresin, Raffaele Parrozzani, Elisabetta Pilotto and Edoardo Midena
J. Clin. Med. 2021, 10(14), 3134; https://doi.org/10.3390/jcm10143134 - 15 Jul 2021
Cited by 23 | Viewed by 2162
Abstract
Subthreshold micropulse laser treatment has become a recognized option in the therapeutic approach to diabetic macular edema. However, some yet undefined elements pertaining to its mechanism of action and most effective treatment method still limit its clinical diffusion. We reviewed the current literature [...] Read more.
Subthreshold micropulse laser treatment has become a recognized option in the therapeutic approach to diabetic macular edema. However, some yet undefined elements pertaining to its mechanism of action and most effective treatment method still limit its clinical diffusion. We reviewed the current literature on subthreshold micropulse laser treatment, particularly focusing on its effects on the modulation of retinal neuroinflammation. Subthreshold micropulse laser treatment seems to determine a long-term normalization of specific retinal neuroinflammatory metabolic pathways, contributing to the restoration of retinal homeostasis and the curtailing of local inflammatory processes. Optimized and standardized parameters ensure effective and safe treatment. Full article
(This article belongs to the Special Issue State-of-the-Art Research on Diabetic Retinopathy)
18 pages, 964 KiB  
Review
Proteomic Analyses of Vitreous in Proliferative Diabetic Retinopathy: Prior Studies and Future Outlook
by Sarah R. Weber, Yuanjun Zhao, Christopher Gates, Jingqun Ma, Felipe da Veiga Leprevost, Venkatesha Basrur, Alexey I. Nesvizhskii, Thomas W. Gardner and Jeffrey M. Sundstrom
J. Clin. Med. 2021, 10(11), 2309; https://doi.org/10.3390/jcm10112309 - 25 May 2021
Cited by 6 | Viewed by 2777
Abstract
Vitreous fluid is becoming an increasingly popular medium for the study of retinal disease. Numerous studies have demonstrated that proteomic analysis of the vitreous from patients with proliferative diabetic retinopathy yields valuable molecular information regarding known and novel proteins and pathways involved in [...] Read more.
Vitreous fluid is becoming an increasingly popular medium for the study of retinal disease. Numerous studies have demonstrated that proteomic analysis of the vitreous from patients with proliferative diabetic retinopathy yields valuable molecular information regarding known and novel proteins and pathways involved in this disease. However, there is no standardized methodology for vitreous proteomic studies. Here, we share a suggested protocol for such studies and outline the various experimental and analytic methods that are currently available. We also review prior mass spectrometry-based proteomic studies of the vitreous from patients with proliferative diabetic retinopathy, discuss common pitfalls of these studies, and propose next steps for moving the field forward. Full article
(This article belongs to the Special Issue State-of-the-Art Research on Diabetic Retinopathy)
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13 pages, 1387 KiB  
Review
Integrative Biology of Diabetic Retinal Disease: Lessons from Diabetic Kidney Disease
by Warren W. Pan, Thomas W. Gardner and Jennifer L. Harder
J. Clin. Med. 2021, 10(6), 1254; https://doi.org/10.3390/jcm10061254 - 18 Mar 2021
Cited by 8 | Viewed by 2579
Abstract
Diabetic retinal disease (DRD) remains the most common cause of vision loss in adults of working age. Progress on the development of new therapies for DRD has been limited by the complexity of the human eye, which constrains the utility of traditional research [...] Read more.
Diabetic retinal disease (DRD) remains the most common cause of vision loss in adults of working age. Progress on the development of new therapies for DRD has been limited by the complexity of the human eye, which constrains the utility of traditional research techniques, including animal and tissue culture models—a problem shared by those in the field of kidney disease research. By contrast, significant progress in the study of diabetic kidney disease (DKD) has resulted from the successful employment of systems biology approaches. Systems biology is widely used to comprehensively understand complex human diseases through the unbiased integration of genetic, environmental, and phenotypic aspects of the disease with the functional and structural manifestations of the disease. The application of a systems biology approach to DRD may help to clarify the molecular basis of the disease and its progression. Acquiring this type of information might enable the development of personalized treatment approaches, with the goal of discovering new therapies targeted to an individual’s specific DRD pathophysiology and phenotype. Furthermore, recent efforts have revealed shared and distinct pathways and molecular targets of DRD and DKD, highlighting the complex pathophysiology of these diseases and raising the possibility of therapeutics beneficial to both organs. The objective of this review is to survey the current understanding of DRD pathophysiology and to demonstrate the investigative approaches currently applied to DKD that could promote a more thorough understanding of the structure, function, and progression of DRD. Full article
(This article belongs to the Special Issue State-of-the-Art Research on Diabetic Retinopathy)
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