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Biomedicines
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Molecular Research and Recent Advances in Diabetic Retinopathy: Second Edition
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Molecular Research and Recent Advances in Diabetic Retinopathy: Second Edition

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: 15 June 2025 | Viewed by 7674

Special Issue Editors

Dr. Tomislav Bulum

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Guest Editor
1. Vuk Vrhovac Univerity Clinic, Merkur University Hospital, Zajčeva 19, 10000 Zagreb, Croatia
2. Medical Faculty, University of Zagreb, Šalata 2, 10000 Zagreb, Croatia
Interests: diabetes type 1; diabetes type 2; metabolic syndrome; diabetic nephropathy; diabetic retinopathy
Special Issues, Collections and Topics in MDPI journals
Dr. Martina Tomić

E-Mail Website
Guest Editor
Vuk Vrhovac University Clinic for Diabetes, Endocrinology and Metabolic Diseases, Merkur University Hospital, 10000 Zagreb, Croatia
Interests: diabetic retinopathy; prevention; retinopathy screening
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Diabetes symbolizes one of the most challenging health problems of the 21st century and is projected to affect 700 million people by 2045. The most devastating components of diabetes are its chronic complications, which lead to a high risk of morbidity and mortality, and an increased health system cost burden. A frequent long-term microvascular complication of type 1 and type 2 diabetes is diabetic retinopathy (DR), which is the leading cause of preventable blindness in working-age adults worldwide. The most pronounced risk factors for developing DR and its progression are longer diabetes duration, hyperglycemia, and hypertension. Besides these traditional risk factors, multiple cellular pathways and potential molecular mechanisms have also been implicated in diabetes-induced complications. These mechanisms include increased polyol pathway flux, increased advanced glycation end-product formation, abnormal protein kinase C activation, activation of the diacyl–glycerol pathway, and increased oxidative stress. In addition, aldose reductase, endothelial nitric oxide synthase, vascular endothelial growth factor, angiotensin conversion, and plasminogen activator inhibitor 1 are some of the genes associated with the development of DR. Despite the declining trend of new visual impairment and blindness due to DR in developed countries over the past decades, it is still the leading cause of blindness in working-age people.

In light of this, we welcome submissions to this Special Issue that focus on molecular research and recent advances in DR. A thorough understanding of this harmful microvascular complication of diabetes is crucial to reduce the risk of blindness and disability in patients with diabetes.

Dr. Tomislav Bulum
Dr. Martina Tomić
Guest Editors

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. Biomedicines is an international peer-reviewed open access monthly 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

  • diabetes
  • diabetic retinopathy
  • complications
  • vascular endothelial growth factor
  • retina
  • biomarkers

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Related Special Issue

Published Papers (7 papers)

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Editorial

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5 pages, 183 KiB  
Editorial
Editorial of the Special Issue “Molecular Research and Recent Advances in Diabetic Retinopathy”
by Tomislav Bulum and Martina Tomić
Biomedicines 2024, 12(8), 1879; https://doi.org/10.3390/biomedicines12081879 - 16 Aug 2024
Viewed by 1056
Abstract
Despite increasing awareness of diabetes and its devastating complications, it remains the most rapidly escalating global health issue [...] Full article
(This article belongs to the Special Issue Molecular Research and Recent Advances in Diabetic Retinopathy: Second Edition)

Research

Jump to: Editorial, Other

11 pages, 1396 KiB  
Article
Association Between Macular Ganglion Cell-Inner Plexiform Layer and Non-Proliferative Retinopathy Without Macular Edema in Type 2 Diabetes via Diabetes Duration and HbA1c Link
by Romano Vrabec, Tomislav Bulum, Spomenka Ljubić and Martina Tomić
Biomedicines 2025, 13(2), 398; https://doi.org/10.3390/biomedicines13020398 - 7 Feb 2025
Viewed by 611
Abstract
Background/Objectives: This study aimed to evaluate the association between the thickness of the macular ganglion cell-inner plexiform layer (GC-IPL), a marker of retinal neurodegeneration, and diabetic retinopathy (DR), a microvasculopathy, in type 2 diabetic patients (T2DM), and to determine the related risk factors. [...] Read more.
Background/Objectives: This study aimed to evaluate the association between the thickness of the macular ganglion cell-inner plexiform layer (GC-IPL), a marker of retinal neurodegeneration, and diabetic retinopathy (DR), a microvasculopathy, in type 2 diabetic patients (T2DM), and to determine the related risk factors. Methods: This cross-sectional study included 50 eyes of 25 T2DM with a median age of 64 and a median diabetes duration of 13 years. Complete diabetological, nephrological, and ophthalmological examination was performed, including color fundus photography according to the EURODIAB methodology and optical coherence tomography (OCT) of the macula. Patients with proliferative DR and diabetic macular edema were not included in the study. Data were analyzed using the software package Statistica™ 14.0.1.25 (TIBCO Inc., USA). Results: Fifty eyes were divided into two groups: no DR (n = 34) and non-proliferative DR (NPDR) (n = 16). The NPDR group had longer diabetes duration (p = 0.042), higher HbA1c (p = 0.002), lower HDL cholesterol (p = 0.036), and also lower macular GC-IPL thickness (p = 0.027) than those without DR. The correlation between DR and GC-IPL was significantly negative (R = −0.319, p = 0.024). DR was positively related to diabetes duration (p = 0.047) and HbA1c (p = 0.003), while the relation between GC-IPL and diabetes duration (p = 0.042) and HbA1c (p = 0.043) was negative. Binary logistic regression analysis showed that HbA1c (OR = 2.77, p = 0.007) and HDL cholesterol (OR = 0.08, p = 0.031) were the main predictors for DR, whereas the best model for predicting the GC-IPL thickness (R2 = 0.223) obtained from stepwise regression analysis included HDL cholesterol, triglycerides, estimated glomerular filtration rate, and albumin/creatinine ratio. Conclusions: The negative correlation between macular GC-IPL and DR in T2DM indicates the coexistence of two parts, neurodegenerative and microvascular, in one diabetic eye complication, linked by the same well-known risk factors: diabetes duration and HbA1c. Full article
(This article belongs to the Special Issue Molecular Research and Recent Advances in Diabetic Retinopathy: Second Edition)
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23 pages, 7241 KiB  
Article
A Novel Ensemble Meta-Model for Enhanced Retinal Blood Vessel Segmentation Using Deep Learning Architectures
by Mohamed Chetoui and Moulay A. Akhloufi
Biomedicines 2025, 13(1), 141; https://doi.org/10.3390/biomedicines13010141 - 9 Jan 2025
Viewed by 906
Abstract
Background: Retinal blood vessel segmentation plays an important role in diagnosing retinal diseases such as diabetic retinopathy, glaucoma, and hypertensive retinopathy. Accurate segmentation of blood vessels in retinal images presents a challenging task due to noise, low contrast, and the complex morphology of [...] Read more.
Background: Retinal blood vessel segmentation plays an important role in diagnosing retinal diseases such as diabetic retinopathy, glaucoma, and hypertensive retinopathy. Accurate segmentation of blood vessels in retinal images presents a challenging task due to noise, low contrast, and the complex morphology of blood vessel structures. Methods: In this study, we propose a novel ensemble learning framework combining four deep learning architectures: U-Net, ResNet50, U-Net with a ResNet50 backbone, and U-Net with a transformer block. Each architecture is customized to enhance feature extraction and segmentation performance. The models are trained on the DRIVE and STARE datasets to improve the degree of generalization and evaluated using the performance metric accuracy, F1-Score, sensitivity, specificity, and AUC. Results: The ensemble meta-model integrates predictions from these architectures using a stacking approach, achieving state-of-the-art performance with an accuracy of 0.9778, an AUC of 0.9912, and an F1-Score of 0.8231. These results demonstrate the performance of the proposed technique in identifying thin retinal blood vessels. Conclusions: A comparative analysis using qualitative and quantitative results with individual models highlights the robustness of the ensemble framework, especially under conditions of noise and poor visibility. Full article
(This article belongs to the Special Issue Molecular Research and Recent Advances in Diabetic Retinopathy: Second Edition)
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11 pages, 2171 KiB  
Article
Microvascular Metrics on Diabetic Retinopathy Severity: Analysis of Diabetic Eye Images from Real-World Data
by Cristina Cuscó, Pau Esteve-Bricullé, Ana Almazán-Moga, Jimena Fernández-Carneado and Berta Ponsati
Biomedicines 2024, 12(12), 2753; https://doi.org/10.3390/biomedicines12122753 - 2 Dec 2024
Cited by 1 | Viewed by 1168
Abstract
Objective: To quantify microvascular lesions in a large real-world data (RWD) set, based on single central retinal fundus images of diabetic eyes from different origins, with the aim of validating its use as a precision tool for classifying diabetic retinopathy (DR) severity. Design: [...] Read more.
Objective: To quantify microvascular lesions in a large real-world data (RWD) set, based on single central retinal fundus images of diabetic eyes from different origins, with the aim of validating its use as a precision tool for classifying diabetic retinopathy (DR) severity. Design: Retrospective meta-analysis across multiple fundus image datasets. Sample size: The study analyzed 2445 retinal fundus images from diabetic patients across four diverse RWD international datasets, including populations from Spain, India, China and the US. Intervention: The quantification of specific microvascular lesions: microaneurysms (MAs), hemorrhages (Hmas) and hard exudates (HEs) using advanced automated image analysis techniques on central retinal images to validate reliable metrics for DR severity assessment. The images were pre-classified in the DR severity levels as defined by the International Clinical Diabetic Retinopathy (ICDR) scale. Main Outcome Measures: The primary variables measured were the number of MAs, Hmas, red lesions (RLs) and HEs. These counts were related with DR severity levels using statistical methods to validate the relationship between lesion counts and disease severity. Results: The analysis revealed a robust and statistically significant increase (p < 0.001) in the number of microvascular lesions and the DR severity across all datasets. Tight data distributions were reported for MAs, Hmas and RLs, supporting the reliability of lesion quantification for accurately assessing DR severity. HEs also followed a similar pattern, but with a broader dispersion of data. Data used in this study are consistent with the definition of the DR severity levels established by the ICDR guidelines. Conclusions: The statistically significant increase in the number of microvascular lesions across DR severity validate the use of lesion quantification in a single central retinal field as a key biomarker for disease classification and assessment. This quantification method demonstrates an improvement over traditional assessment scales, providing a quantitative microvascular metric that enhances the precision of disease classification and patient monitoring. The inclusion of a numerical component allows for the detection of subtle variations within the same severity level, offering a deeper understanding of disease progression. The consistency of results across diverse datasets not only confirms the method’s reliability but also its applicability in a global healthcare setting. Full article
(This article belongs to the Special Issue Molecular Research and Recent Advances in Diabetic Retinopathy: Second Edition)
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15 pages, 5714 KiB  
Article
Metabolic, Microvascular, and Structural Predictors of Long-Term Functional Changes Evaluated by Multifocal Electroretinogram in Type 1 Diabetes
by Mariacristina Parravano, Serena Fragiotta, Eliana Costanzo, Fabiana Picconi, Paola Giorno, Daniele De Geronimo, Daniela Giannini, Monica Varano, Vincenzo Parisi and Lucia Ziccardi
Biomedicines 2024, 12(11), 2614; https://doi.org/10.3390/biomedicines12112614 - 15 Nov 2024
Viewed by 923
Abstract
Background: This study aimed to analyze the potential pathogenic connection between metabolic factors, photoreceptor cell rearrangements, retinal microvascular perfusion, and functional parameters through multifocal electroretinography (mfERG) in type 1 diabetes mellitus (DM1). Methods: This prospective observational cohort study enrolled DM1 patients (40.5 ± [...] Read more.
Background: This study aimed to analyze the potential pathogenic connection between metabolic factors, photoreceptor cell rearrangements, retinal microvascular perfusion, and functional parameters through multifocal electroretinography (mfERG) in type 1 diabetes mellitus (DM1). Methods: This prospective observational cohort study enrolled DM1 patients (40.5 ± 9.1 years) with mild nonproliferative diabetic retinopathy followed for 4 years. Patients were subjected to multimodal imaging, which included color fundus photography, optical coherence tomography (OCT), OCT angiography, adaptive optics (AO), and mfERG. OCTA slabs were analyzed using ImageJ software (software version 2.3.0/1.53f) to calculate perfusion density (PD) at both superficial (SCP) and deep (DCP) capillary plexuses, as well as flow deficit percentage (FD%) at the choriocapillaris (CC). To calculate cone metrics on AO at the parafovea, including cone density (CD), linear dispersion index (LDi), and heterogeneity packing index (Hpi%) in the parafovea, the images were post-processed using a MATLAB algorithm. The mfERG P1 implicit time (IT) and N1-P1 response amplitude density (RAD) from R1 (foveal area), R2 (parafoveal area), and the unified rings R1 + R2 were evaluated. Results: A total of 22 patients (22 eyes) were enrolled. No significant differences were noted in central mfERG amplitude and implicit time-averaged values (p > 0.05, all). The main factor influencing R1 IT was HbA1c, while R1 RAD was affected by Hpi and CC FD%. R1 + R2 IT was influenced by Hpi, LDi (p > 0.001, all), and modifications in the perfusion density in the SCP (p < 0.001) and DCP (p = 0.03) at the parafovea. In contrast, R1 + R2 RAD were associated with HbA1c (p = 0.02) and Hpi (p < 0.001). Conclusions: Microvascular changes and glucometabolic factors are key elements influencing the long-term morphofunctional alterations at the photoreceptor level in DM1. Full article
(This article belongs to the Special Issue Molecular Research and Recent Advances in Diabetic Retinopathy: Second Edition)
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10 pages, 1486 KiB  
Article
Retinochoroidal Vascular Changes in Long-Term Type 1 Diabetic Patients Assessed by Optic Coherence Tomography Angiography
by Maria Sopeña-Pinilla, Elvira Orduna-Hospital, Maria D. Diaz-Barreda, Ana Boned-Murillo, Guisela Fernandez-Espinosa, Marta Arias-Alvarez, Javier Acha-Perez, Ana Sanchez-Cano and Isabel Pinilla
Biomedicines 2024, 12(8), 1780; https://doi.org/10.3390/biomedicines12081780 - 6 Aug 2024
Viewed by 957
Abstract
To study retinal and choriocapillaris (CC) alterations using optical coherence tomography angiography (OCTA) in long-term type 1 diabetic (DM1) patients without diabetic retinopathy (DR). Seventy-eight eyes from 78 well-controlled DM1 patients diagnosed at least 15 years prior and 130 eyes of 130 healthy [...] Read more.
To study retinal and choriocapillaris (CC) alterations using optical coherence tomography angiography (OCTA) in long-term type 1 diabetic (DM1) patients without diabetic retinopathy (DR). Seventy-eight eyes from 78 well-controlled DM1 patients diagnosed at least 15 years prior and 130 eyes of 130 healthy subjects were included in a cross-sectional descriptive study. Six eyes were excluded from the DM1 group. OCTA with Deep Range Imaging (DRI)-Triton swept source (SS)-OCT was performed. Statistically significant differences were found in all areas of the superficial capillary plexus (SCP), with lower values in DM1 patients. Differences were noted in all quadrants of the deep capillary plexus (DCP) except for the central area. Significant changes in CC blood flow were only found in the center. The foveal avascular zone (FAZ) area and diameters in the SCP were significantly different, while the DCP FAZ area was similar in both groups. Disease duration and microalbuminuria correlated negatively with some SCP areas and positively with FAZ values. Anatomical evaluation revealed microaneurysms in both plexuses, FAZ modifications, and areas lacking blood perfusion. Long-term type 1 diabetic patients without DR display microvascular abnormalities affecting retinal and CC blood perfusion, along with anatomical changes in retinal blood vessels. Full article
(This article belongs to the Special Issue Molecular Research and Recent Advances in Diabetic Retinopathy: Second Edition)
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Other

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19 pages, 1518 KiB  
Systematic Review
Vitamin D Deficiency as a Risk Factor for Diabetic Retinopathy: A Systematic Review and Meta-Analysis
by Claudia Elena Petrea, Laura Andreea Ghenciu, Roxana Iacob, Emil Robert Stoicescu and Dorel Săndesc
Biomedicines 2025, 13(1), 68; https://doi.org/10.3390/biomedicines13010068 - 30 Dec 2024
Viewed by 980
Abstract
Diabetic retinopathy (DR), a significant microvascular complication of diabetes mellitus (DM), remains a major cause of vision loss worldwide. Vitamin D, recognized for its role in bone health, has also been implicated in various non-skeletal conditions, including DR. This systematic review analyzed data [...] Read more.
Diabetic retinopathy (DR), a significant microvascular complication of diabetes mellitus (DM), remains a major cause of vision loss worldwide. Vitamin D, recognized for its role in bone health, has also been implicated in various non-skeletal conditions, including DR. This systematic review analyzed data from 20 studies involving 22,408 participants to explore the relationship between vitamin D levels and DR. Studies were included based on strict eligibility criteria, ensuring they could distinctly classify participants into DR and non-DR groups and provide quantitative measurements of vitamin D levels. Of these, nine studies were included in the meta-analysis. The pooled analysis revealed a significant association between lower vitamin D levels and increased odds of DR, with a combined odds ratio (OR) of 1.15 (95% CI: 1.10–1.20) under the fixed-effects model and 1.17 (95% CI: 1.08–1.27) under the random-effects model. Mean serum vitamin D levels were lower in individuals with DR (18.11 ± 5.35 ng/mL) compared to those without DR (19.71 ± 7.44 ng/mL), with a progressive decline observed across DR severity stages. Subgroup analyses showed significantly lower levels of vitamin D in proliferative DR compared to non-proliferative stages. Heterogeneity (I2 = 89%) was noted, most probably due to geographic differences, varying methodologies for vitamin D measurement, and DR classification approaches. Secondary analyses indicated that vitamin D deficiency prevalence ranged from 27% to 95% in DR populations, highlighting its potential role in disease progression. This review highlights the need for longitudinal studies to better understand the causal relationship. The findings also call attention to a critical gap in the literature regarding the therapeutic role of vitamin D supplementation in preventing and managing DR. Addressing vitamin D deficiency as a modifiable risk factor in DM care may offer new avenues for reducing the burden of DR. Full article
(This article belongs to the Special Issue Molecular Research and Recent Advances in Diabetic Retinopathy: Second Edition)
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