Search Results (877)

Chronic hyperglycemia disrupts the retinal neurovascular unit, making diabetic retinopathy (DR) the leading cause of adult vision loss. The hallmarks of DR include pathological angiogenesis, vascular leakage, and neurodegeneration. Although vascular endothelial growth factor A (VEGF-A) is a key mediator of these abnormalities and anti-VEGF therapies remain the standard treatment, many patients exhibit incomplete responses, and these therapies do not adequately address inflammation or fibrosis. Placental growth factor (PlGF), a VEGF family member that selectively binds to VEGFR1, has emerged as an important contributor to retinal neovascularization, vascular dysfunction, barrier breakdown, and microinflammation in DR. Unlike VEGF-A, PlGF modulates distinct responses among retinal neurons, glial cells, and vascular cells, with its abnormal expression closely associated with disease progression from non-proliferative to proliferative DR. This review summarizes the context-dependent functions of PlGF in the diabetic retina, compares PlGF–VEGFR1 signaling with VEGF-A–VEGFR2 pathways, and discusses preclinical and clinical evidence supporting PlGF inhibition as a potential complementary approach to existing anti-VEGF therapy. Full article

In recent years, the role of non-coding RNAs in human physiology and pathology has emerged as an essential avenue of investigation. Among others, studies identifying the biological role of microRNAs (miRNAs) have paved the way for future inquiries on the importance and biological significance of non-coding RNAs. In this review, we provide an overview of miRNAs’ biology and their contribution to the pathogenesis of diabetic retinopathy (DR). This complication of diabetes is the leading cause of blindness in adults, affecting more than 4 million people in the US alone and over 103 million people worldwide. Despite the tremendous efforts of the scientific community and the pharmaceutical industry, the development of new, more effective therapeutic and diagnostic tools for DR to date remains an unmet need. More than a decade from the initial work assessing miRNA expression profiles in diabetic patients, we have learned the impact of these signaling molecules in DR and garnered knowledge of their complexity and their potential as new diagnostic and therapeutic targets for this potentially blinding condition. Full article

Introduction: Diabetic retinopathy (DR) is characterized by early retinal neurodegeneration accompanied by progressive alterations of the retinal microvasculature, both exacerbated by hyperglycemia-induced oxidative stress and inflammation. Mitochondrial dysfunction critically contributes to neuronal loss and vascular impairment. The 18 kDa Translocator Protein (TSPO) is a mitochondrial outer membrane protein whose expression is increased in activated retinal glial cells and represents a promising target to modulate neuroinflammation and oxidative stress. This study evaluates the therapeutic potential of the TSPO ligand PIGA-1138 in experimental models of DR. Methods: PIGA-1138 (3 µM in vitro; 10 mg/kg/day, i.p., in vivo) was evaluated in high glucose (HG)-exposed 661W retinal cells and in streptozotocin (STZ, 150 mg/kg)-induced diabetic C57BL/6J mice. Cell viability, mitochondrial function, oxidative stress, and Nrf2, HO-1, and SOD1 expression were assessed in vitro. Retinal function and morphology were evaluated in vivo by electroretinography (ERG), visual acuity testing, and optical coherence tomography (OCT) at 30 and 60 days after diabetes induction. Results: PIGA-1138 significantly improved cell viability, reducing apoptosis (TUNEL p ≤ 0.01), preserving mitochondrial membrane potential (MitoRed p ≤ 0.01), reducing oxidative damage, and enhancing Nrf2 nuclear translocation together with HO-1 (p ≤ 0.05) and SOD1 (p ≤ 0.01) expression in HG-treated retinal cells. In diabetic mice, treatment preserved ERG responses and limited retinal thinning at 60 days (p ≤ 0.01), while showing a trend toward preserving visual acuity. Conclusions: Targeting mitochondrial TSPO with PIGA-1138 attenuates key hallmarks of DR by mitigating oxidative stress, suppressing neuroinflammation, and preserving retinal structure and function. These findings support TSPO as a potential disease-modifying target for DR. Full article

Background: Non-proliferative diabetic retinopathy (NPDR) is a common microvascular complication of type 2 diabetes mellitus (T2DM) associated with chronic inflammation, metabolic dysregulation, and multiple interacting systemic factors. This study evaluated the associations of inflammatory biomarkers, serum 25-hydroxyvitamin D [25(OH)D], electrolyte homeostasis, and lipid-derived indices with NPDR. Methods: In this cross-sectional study with prospective recruitment, 98 patients with T2DM were classified into NPDR (n = 55) and non-DR (n = 43) groups. Clinical characteristics, hematological inflammatory indices, serum interleukin-6 (IL-6), C-reactive protein (CRP), 25(OH)D, electrolyte concentrations, lipid profile, and derived biomarkers—including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune–inflammation index (SII), LDL-C/HDL-C ratio, and calculated serum osmolarity—were compared. Receiver operating characteristic (ROC) analysis and multivariable logistic regression were performed to assess discriminatory performance and independent associations with NPDR. Results: Patients with NPDR had significantly lower serum 25(OH)D concentrations than the non-DR group (16.6 ± 7.5 vs. 21.0 ± 5.2 ng/mL, p < 0.001). Serum IL-6 levels (4.2 ± 3.1 vs. 2.8 ± 1.4 pg/mL, p = 0.047), NLR (p = 0.043), LDL-C/HDL-C ratio (p = 0.031), and calculated serum osmolarity (p = 0.033) were significantly higher, whereas lymphocyte count and the lymphocyte-to-monocyte ratio were significantly lower. Among individual biomarkers, serum 25(OH)D showed the best discriminatory performance (AUC = 0.712). A multivariable model including insulin therapy, IL-6, serum 25(OH)D, and the LDL-C/HDL-C ratio demonstrated good discrimination (AUC = 0.813), with 81.8% sensitivity and 81.4% specificity. Bootstrap validation supported the stability of the model. Conclusions: NPDR was associated with lower serum 25(OH)D concentrations, systemic inflammation, and a less favorable LDL-C/HDL-C ratio. A multivariable model integrating inflammatory, metabolic, and nutritional biomarkers showed better discriminatory performance than individual biomarkers. The association between insulin therapy and NPDR likely reflects greater diabetes severity rather than a direct effect of insulin. These findings are exploratory, and prospective studies in larger independent cohorts are needed to determine whether these biomarkers improve risk stratification beyond established clinical factors. Full article

Background/Objectives: The hemoglobin–albumin–lymphocyte–platelet (HALP) score combines routine laboratory measures into an index of systemic immune–nutritional status. Its relationship with graded diabetic retinopathy (DR) severity is not fully established. We compared HALP between patients with DR and ophthalmology controls without documented diabetes and examined its association with retinopathy stage and proliferative disease. Methods: This prospective single-center case–control study enrolled 209 consecutive adults: 105 patients with DR and 104 controls. DR was recorded across eight ordered stages and additionally classified as non-proliferative DR (NPDR) or proliferative DR (PDR). Between-group tests, Spearman correlation, logistic regression, and receiver operating characteristic analysis were used. Results: HALP was lower in the DR group than in controls (47.47 [26.44] vs. 52.67 [31.83], p = 0.048) and in PDR than in NPDR (45.98 [17.62] vs. 52.90 [42.49], p = 0.008). HALP declined modestly with increasing stage (rho = −0.260, p = 0.007). In an exploratory age- and sex-adjusted model, each 10-unit increase in HALP was associated with lower odds of case-group membership (OR = 0.850, 95% CI: 0.750–0.963; p = 0.011). Within the DR cohort, HALP was not significantly associated with PDR after adjustment for age, sex, and HbA1c (OR = 0.809, 95% CI: 0.640–1.023; p = 0.077). Discrimination between cases and controls was limited (AUC = 0.579); a threshold of ≤52.09 provided 62.9% sensitivity and 53.8% specificity. Conclusions: Lower HALP values accompanied DR case status and greater retinopathy severity, but the adjusted association with PDR was not significant. Because diabetes status differed between groups, the case–control finding may reflect systemic effects of diabetes as well as retinal involvement. Full article

Background: Diabetic retinopathy (DR) is the most prevalent microvascular complication of type 2 diabetes mellitus (T2DM) and a recognised marker of systemic vascular injury. Whether DR—graded independently by two experienced ophthalmologists as part of routine institutional care—is independently associated with concurrent nephropathy (urine albumin-to-creatinine ratio [UACR] ≥ 30 mg/g) and subclinical cardiac stress (N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≥ 125 pg/mL) remains insufficiently examined. Methods: Retrospective cross-sectional study of 401 T2DM adults who underwent dilated fundus examination independently graded by two board-certified ophthalmologists (each ≥ 10 years’ experience in diabetic eye disease) using ETDRS-based classification. Inter-physician agreement was quantified by Cohen’s weighted kappa. The primary composite outcome was concurrent nephropathy and subclinical cardiac stress. Multivariable logistic regression adjusted for age, sex, HbA1c, diabetes duration, eGFR, hypertension, and pharmacological treatments. Results: The composite outcome was present in 120 (64.2%) DR-positive vs. 14 (6.5%) DR-negative patients (crude OR: 25.59 (13.78–47.51); p < 0.001; fully adjusted OR: 21.49 (11.02–41.81); p < 0.001). Inter-physician agreement was high (Cohen’s weighted κ = 0.88; 95% CI: 0.83–0.93). Nephropathy alone was found in 164 (87.7%) vs. 76 (35.5%) patients (OR: 12.95 (7.71–21.75); p < 0.001), and elevated NT-proBNP in 137 (73.3%) vs. 39 (18.2%) patients (OR: 12.29 (7.65–19.76); p < 0.001). A significant trend across DR severity grades was observed (p for trend < 0.001), although the gradient was not strictly monotonic. ROC AUC = 0.837 (95% CI: 0.784–0.860). Conclusions: Ophthalmologist-graded DR was independently associated with the concurrent presence of albuminuria and elevated NT-proBNP in T2DM. Because the design is cross-sectional, these findings describe association rather than prediction or causation. They generate the hypothesis that retinal grading may help flag patients in whom cardiorenal biomarker assessment is worth considering, but prospective validation is required before any screening application. Full article

Diabetic retinopathy (DR) is one of the main causes of vision impairment globally, and it is increasingly recognized as a neurovascular disease characterized by both microvascular and neural dysfunction. Traditional assessment approaches primarily focus on structural retinal alterations and visual acuity, which may fail to identify early functional impairments. Contrast sensitivity (CS), which measures the capacity to distinguish subtle luminance differences, is increasingly recognized as an early manifestation of retinal dysfunction in diabetes mellitus. This narrative review seeks to describe current knowledge on the role of CS in DR, including its pathophysiological foundation, clinical importance, and link to structural retinal alterations. A systematic literature search of PubMed, Scopus, and Google Scholar (2000–2026) was performed to identify studies on CS in diabetes mellitus and diabetic retinopathy. Multiple investigations found that diabetic patients, including those with no clinically evident DR and normal visual acuity, had lower contrast sensitivity. CS impairment was associated with retinal neurodegeneration, ganglion cell dysfunction, microvascular alterations, and diabetic macular edema severity. OCT and OCT-A findings showed important structure–function correlations between reduced CS and retinal thinning, capillary dropout, and impaired perfusion. CS testing may provide additional functional information beyond standard visual acuity assessment and may improve early disease detection and monitoring. In conclusion, contrast sensitivity represents a promising functional biomarker for early diabetic retinal dysfunction and may complement structural imaging and visual acuity testing in DR evaluation. Although methodological variability currently limits widespread clinical implementation, advances in digital technologies and multimodal assessment strategies may facilitate its future integration into routine ophthalmologic practice. Full article

Diabetic retinopathy (DR) and glaucoma, globally leading causes of irreversible blindness, can be detected and managed early with timely screening. In low-resource settings, access to ophthalmological examination is limited by a variety of constraints, including scarcity of specialists, equipment costs, geographic distance from care centers, and limited patient awareness. This narrative review examines the principal barriers to early detection of glaucoma and DR and evaluates evidence-based strategies to overcome them, including low-cost portable ophthalmic testing tools, artificial intelligence (AI) analytics, risk-based resource allocation, teleophthalmology, and targeted patient education. In different populations, these strategies have been shown to meaningfully increase access to ophthalmologic screening and follow-up at a significantly lower cost. We describe these approaches, demonstrate previously successful initiatives, and propose various combined approaches adapted to the specific needs of the various low-resource settings. Full article

Background/Objectives: The clinical profile of serum Maresin-1 (MaR1) in relation to diabetic retinopathy phenotypes and proteinuria in type 2 diabetes mellitus (T2DM) remains unclear. We evaluated serum MaR1 across healthy controls and patients with T2DM without diabetic retinopathy (DR), non-proliferative DR (NPDR), or proliferative DR (PDR), and examined the relationship between MaR1 and the urine protein-to-creatinine ratio (UPCR). Methods: This single-center cross-sectional study included 93 participants. Serum MaR1 was measured by ELISA. Group differences were assessed with the Kruskal–Wallis test and Holm-adjusted post hoc tests. DR phenotypes were analyzed among patients with T2DM. The MaR1-UPCR relationship was examined using correlation and adjusted regression models. Results: MaR1 differed across groups (H = 49.36, p < 0.001, epsilon² = 0.521). The median MaR1 was 89.8 (82.8–97.2) pg/mL in controls and 34.3 (33.0–36.0), 35.8 (34.4–36.7), and 34.0 (33.1–35.7) pg/mL in T2DM without DR, NPDR, and PDR, respectively. MaR1 was higher in controls than in all T2DM groups, whereas T2DM groups did not differ. Within T2DM, MaR1 was not associated with DR stage (H = 4.44, p = 0.109; rho = −0.001, p = 0.996). MaR1 was inversely related to the UPCR overall (rho = −0.272, p = 0.008), but not within T2DM (rho = −0.057, p = 0.634) or in adjusted models. Conclusions: MaR1 was markedly lower in T2DM than in controls. This reduction was not explained by DR stage or proteinuria. These findings indicate that MaR1 should be interpreted as a T2DM-associated systemic alteration rather than as a marker of retinopathy stage or proteinuria. Full article

Diabetic retinopathy (DR) is the leading cause of vision loss in early adulthood, caused by disruption of the retinal microvasculature. In the early stages of DR, there is a loss of pericytes, the cells responsible for maintaining vascular stability. Pericytes are progenitor cells and possess stem cell properties such as the potential to differentiate into various cell types, surface markers similar to mesenchymal stem cells (MSCs), and the ability to modulate the immune response. Human adipose-derived MSCs, when cultured with certain growth factors, acquire a pericyte-like phenotype, which expands the potential for pericyte applications in therapy. Current treatments for DR include anti-vascular endothelial growth factor agents, corticosteroids, and laser photocoagulation. All of these treatments are symptomatic and have adverse effects. This review covers the prevalence of DR in Kazakhstan and worldwide, the pathogenesis of the disease at the molecular and clinical level, treatment methods and modern approaches based on stem cells and pericytes. Full article

Diabetic retinopathy (DR) grading requires reliable five-grade severity assessment under substantial acquisition variability and cross-dataset distribution shift. We propose PRISM-DR, a multi-objective five-grade DR grading framework trained under a gradient-partitioned strategy. The architecture is organized as a feedforward pipeline: a data-driven preprocessing stage followed by a ConvNeXtV2-Base backbone, a Recurrent BiFPN neck for multi-scale feature fusion, a Frequency-Aware Fusion module, a lightweight multi-scale reasoning transformer, dual classification heads with gradient-isolated pathways (categorical and ordinal), and a prototype memory module for embedding regularization. The CORAL ordinal head operates through a dedicated projection layer and is gradient-isolated from the backbone; the backbone is shaped by the cross-entropy, prototype contrastive, and view-consistency objectives, which carry indirect ordinal signal through severity-weighted class penalties and grade-indexed cluster regularization. The model is trained in a multi-crop setting with a phased loss curriculum designed for severely imbalanced DR datasets. Evaluated across six datasets under Fixed-Source, Multi-Target (FSMT) protocols, PRISM-DR trained on EyePACS + DDR achieves QWK of 0.835 on IDRiD, 0.865 on APTOS2019, and 0.720 on Messidor-2, with in-domain QWK = 0.920 and AUC-PR = 0.941 on EyePACS, outperforming RETFound, RETFound-Green, and MedGemma-4B in AUC-PR across all evaluated datasets. Quantitative interpretability evaluation against 755 expert-annotated lesion images yields 8.0× Energy Ratio Enrichment and a FAF gate retention ratio of 4.4× inside lesion regions, confirming that anatomically plausible spatial priors emerge from grade-level supervision alone, without pixel-level annotation. PRISM-DR establishes a superior accuracy–robustness–capacity trade-off for scalable, automated DR screening. Full article

Background/Objectives: The relationship between hyperuricemia and diabetic retinopathy (DR) remains controversial despite both conditions being associated with vascular endothelial dysfunction. This study aimed to investigate the longitudinal association between hyperuricemia and the onset and progression of DR in patients with type 2 diabetes mellitus (T2D). Methods: We conducted a retrospective cohort study using patient data from initial visits between 2005 and 2022. Patients were categorized at baseline as having no DR (NDR), simple DR (SDR). The primary endpoint was the onset of DR from NDR, and the secondary endpoint was the progression of DR from SDR. Kaplan–Meier and Cox proportional hazards analyses were employed for statistical evaluation. Results: The study included 1972 patients (1702 with NDR and 270 SDR). In the overall NDR cohort, hyperuricemia was not significantly associated with the onset or progression of DR. However, upon stratification by baseline HbA1c, hyperuricemia was significantly associated with a higher incidence of DR within the high-HbA1c subgroup (≥9%) of the NDR cohort (HR 2.40, 95% CI [1.27–4.55]). Similarly, within the SDR cohort, a Kaplan–Meier analysis demonstrated a significantly higher rate of DR progression in the hyperuricemia group, exclusively among patients with HbA1c ≥ 9% (p = 0.01). Conclusions: Hyperuricemia is independently associated with the onset and progression of DR in T2D patients with poor glycemic control While often co-occurring with other DR risk factors, hyperuricemia may serve as a potential marker for the development of retinopathy in this high-risk population. Full article

Background/Objectives: Diabetic Retinopathy (DR) is a prevalent and severe complication of diabetes, caused by prolonged hyperglycemia that damages retinal microvasculature and may ultimately lead to vision loss or blindness. While convolutional neural networks (CNNs) have shown promise in automating DR detection via retinal imaging, traditional approaches often suffer from limited diagnostic accuracy, long training times, and reliance on small or imbalanced datasets. Objective: This study evaluates an integrated transfer-learning using adaptive training strategies for multiclass retinal image classification. Methods: The proposed framework integrates transfer learning, feature-space dimensionality reduction, and adaptive training strategies based on an ImageNet pretrained ResNet50 backbone to improve training stability, computational efficiency, and multiclass retinal image classification performance. Results: The proposed Transfer Learning (TL)-based model was trained and evaluated on a large, publicly available dataset of retinal images, achieving an overall accuracy of 84%, maximum class-specific accuracy of 89%, sensitivity of up to 97%, and an F1-score of 92%. These results demonstrate reasonable overall classification performance under constrained data conditions. Conclusions: The proposed framework demonstrates the feasibility of integrating transfer learning and adaptive training strategies for multiclass retinal image classification under constrained benchmark conditions. However, the study is limited by the use of heavily downsampled retinal images, and further validation on high-resolution clinical datasets is required before practical deployment. Future methodological refinement and validation on high-resolution clinical datasets may support development of computer-assisted retinal image analysis systems. Full article

Diabetic retinopathy (DR) reflects retinal microvascular injury and systemic immune-metabolic stress, and most public DR transcriptomic datasets lack paired microbiome/metabolomic profiles. We used gutMGene v2.0 as a curated microbe/metabolite–host gene prior and integrated it with peripheral blood transcriptomics from GSE221521. Candidate genes were refined by weighted gene co-expression network analysis (WGCNA), repeated resampling, cross-dataset assessment, mechanism scoring, peripheral blood mononuclear cell (PBMC) single-cell localization and filamin A (FLNA)-centered single-cell gene regulatory network (GRN) virtual knockout. The gutMGene prior contained 238 host genes; 15 DR-associated genes overlapped this prior, and WGCNA retained ten candidate gut microbe and microbial metabolite-related genes (GMMRGs): FLNA, AKT1, IRAK1, BCL10, CDK6, CTSD, JUP, CXCL1, CXCR2 and IL4R. Resampling prioritized FLNA as the most consistent candidate. Cross-dataset assessment localized the strongest signal to type 2 diabetes (T2D) PBMCs, retinal endothelial cells and advanced proliferative diabetic retinopathy with diabetic macular edema (PDR + DME) retinal tissue, with weaker separation in whole blood, broad retinal tissue and six-donor type 1 diabetes (T1D) PBMCs. FLNA virtual knockout predicted cell-context-dependent perturbation of immune-related transcriptional programs, including IL4R in DR B cells and CTSD in DR monocytes/NK cells. This prior-guided study identifies FLNA within a ten-gene GMMRG set as a circulating host-response signal that links curated microbe/metabolite–host records to immune-vascular and cytoskeletal remodeling in DR. Full article

Diabetic retinopathy (DR) is a leading cause of vision loss, yet its systemic proteomic mediators remain largely elusive. This study aimed to identify causal plasma proteins, map their cell-type-specific localization in the retina, and experimentally validate their expression under disease-relevant stress. We conducted a proteome-wide association study (PWAS) integrating UK Biobank plasma pQTL data (N = 53,022) with DR GWAS summary statistics. Causal relationships were inferred utilizing summary-data-based Mendelian randomization (SMR) and Bayesian colocalization. Prioritized candidates were mapped to the Human and Mouse Retina Cell Atlases via single-nucleus RNA sequencing (snRNA-seq). Finally, to substantiate the computational findings, in vitro validation of COL4A1 was performed in ARPE-19 cells cultured under hyperglycemic conditions utilizing quantitative real-time PCR (qPCR) and transcriptomic dataset re-analysis. The PWAS identified 26 proteins significantly associated with DR. Subsequent causal inference prioritized 12 high-confidence candidates, including GSTT2B, COL4A1, PAM, and GALNT3. Notably, GSTT2B emerged as a Tier-1 protective causal protein (Z = −3.609; P_SMR = 1.22 × 10⁻⁴). snRNA-seq mapping revealed that GSTT2B is robustly expressed in Müller glia and the retinal pigment epithelium (RPE), whereas COL4A1 is prominently enriched in vascular compartments. These specific expression signatures exhibited partial conservation across species with notable cell-type specific variations. Crucially, in vitro validation confirmed that COL4A1 mRNA expression is significantly upregulated under high-glucose stress. Furthermore, druggability analysis highlighted actionable targets, identifying GSTT2B as a highly probable causal mediator and COL4A1 as a prioritized candidate for structural intervention. This study provides robust genetic, single-cell, and experimental evidence implicating specific plasma proteins in DR pathogenesis. The identification of GSTT2B-mediated protective pathways and the hyperglycemia-induced upregulation of COL4A1 offer a high-resolution molecular atlas to guide drug repositioning and precision therapeutic strategies. Full article