Development Of Proliferative Diabetic Retinopathy Research Articles

Use of Diabetes Technologies and Retinopathy in Adults With Type 1 Diabetes

Diabetic retinopathy (DR) is a complication of diabetes that can lead to vision loss. Outcomes of continuous glucose monitoring (CGM) and insulin pump use in DR are not well understood. To assess the use of CGM, insulin pump, or both, and DR and proliferative diabetic retinopathy (PDR) in adults with type 1 diabetes (T1D). A retrospective cohort study of adults with T1D in a tertiary diabetes center and ophthalmology center was conducted from 2013 to 2021, with data analysis performed from June 2022 to April 2023. Use of diabetes technologies, including insulin pump, CGM, and both CGM and insulin pump. The primary outcome was development of DR or PDR. A secondary outcome was the progression of DR for patients in the longitudinal cohort. Multivariable logistic regression models assessed for development of DR and PDR and association with CGM and insulin pump use. A total of 550 adults with T1D were included (median age, 40 [IQR, 28-54] years; 54.4% female; 24.5% Black or African American; and 68.4% White), with a median duration of diabetes of 20 (IQR, 10-30) years, and median hemoglobin A1c (HbA1c) of 7.8% (IQR, 7.0%-8.9%). Overall, 62.7% patients used CGM, 58.2% used an insulin pump, and 47.5% used both; 44% (244 of 550) of the participants had DR at any point during the study. On univariate analysis, CGM use was associated with lower odds of DR and PDR, and CGM with pump was associated with lower odds of PDR (all P < .05), compared with no CGM use. Multivariable logistic regression adjusting for age, sex, race and ethnicity, diabetes duration, microvascular and macrovascular complications, insurance type, and mean HbA1c, showed that CGM was associated with lower odds of DR (odds ratio [OR], 0.52; 95% CI, 0.32-0.84; P = .008) and PDR (OR, 0.42; 95% CI, 0.23-0.75; P = .004), compared with no CGM use. In the longitudinal analysis of participants without baseline PDR, 79 of 363 patients (21.8%) had progression of DR during the study. In this cohort study of adults with T1D, CGM use was associated with lower odds of developing DR and PDR, even after adjusting for HbA1c. These findings suggest that CGM may be useful for diabetes management to mitigate risk for DR and PDR.

Evaluation of Hypoxia and Microcirculation Factors in the Progression of Diabetic Retinopathy.

The purpose of this study was to evaluate comparatively the changes in HIF-1ɑ, EPO, sICAM-1, hemodynamic, and electrophysiological parameters during the progression of non-proliferative diabetic retinopathy (NPDR). This retrospective longitudinal study included 82 patients with NPDR, who were divided into 2 groups: group I (n=40) consisted of patients without progression of NPDR after 1 year and group II (n=42) included patients with the transition of NPDR to proliferative diabetic retinopathy (PDR). The hemodynamics of the eye was assessed by Doppler ultrasonography. The glial hypoxia index Cg was calculated using ERG. The serum levels of hypoxia-inducible factor 1-a (HIF1-α), soluble intercellular adhesion molecule-1 (sICAM-1), and erythropoietin (EPO) were determined by ELISA method. In group II, resistive index (RI), short posterior ciliary arteries (SPCAs) increased significantly from 0.62 ± 0.005 to 0.65 ± 0.007 (P=0.003), being higher than the corresponding parameter in group I (P=0.013). In group II, there was an increase in the hypoxia index Cg (5.56 ± 0.05) relative to the primary indicators and in group I (P<0.001). In group II, HIF1-ɑ, EPO, and sICAM-1 levels after a year significantly increased (0.213 ± 0.02 ng/mL, 37.7 ± 2.4mIU/mL, and 576.3 ± 11.9 ng/mL, respectively) both relative to the main indicators and the values in group I (P<0.001). When EPO exceeds 27.5mIU/mL, a high risk of progression of NPDR to the initial stages of PDR is predicted. The glial Cg index and the level of HIF1-a, EPO in the serum of patients with progression of NPDR were initially higher than in patients without progression of NPDR and have increased during the year, indicating the development of PDR due to more severe hypoxia.

Retinal main vessel calibers and systemic markers for long-term development of proliferative diabetic retinopathy.

To evaluate if retinal vascular calibers and systemic risk factors in patients with no or minimal diabetic retinopathy (DR) can predict risk of long-term progression to proliferative diabetic retinopathy (PDR). This was a matched case-control study of patients with diabetes having no or minimal DR at baseline with (cases) or without (controls) subsequent development of PDR. We collected six-field, 45-degree retinal images, demographic and clinical data from the Funen Diabetes Database. We included 52 eyes from 39 cases and 107 eyes from 89 controls matched on sex, age, type of diabetes, time from first to last screening episode and baseline DR level. Cases had higher HbA1c (73 vs. 55 mmoL/moL; p < 0.001), triglycerides (1.32 vs. 1.16 mmoL/L; p = 0.02) and longer duration of diabetes (19 vs. 14 years; p = 0.01), but the groups did not differ in calibers of retinal arterioles (229 vs. 227 μm; p = 0.49), venules (289 vs. 290 μm; p = 0.83) or the arterio-to-venule ratio (0.78 vs. 0.77; p = 0.86).In a multivariable logistic regression model with cluster robust standard error, HbA1c (OR 1.54 per 10 mmoL/moL; 95%-CI: 1.15-2.07; p = 0.004), triglyceride (OR 1.39 per 1 mmoL/L; 95%-CI: 1.03-1.86; p = 0.03) and duration of diabetes (OR 1.09 per year; 95%-CI: 1.03-1.16; p = 0.003) were independent risk factors for PDR. Retinal vascular calibers did not predict long-term development of PDR in contrast to well-established risk factors like HbA1c, triglyceride and duration of diabetes.

ADAMTS5 promotes neovascularization via autophagic degradation of PEDF in proliferative diabetic retinopathy

Proliferative diabetic retinopathy (PDR) adversely affects visual function. Extracellular matrix proteins (ECM) contribute significantly to the development of PDR. A Disintegrin and Metalloproteinase with Thrombospondin motifs 5 (ADAMTS5) is a member of ECM proteins. ADAMTS5 participates in angiogenesis and inflammation in diverse diseases. However, the role of ADAMTS5 in PDR remains elusive. Multiplex beam array technology was used to analyze vitreous humor of PDR patients and normal people. ELISA and Western blot were used to detect the expression of ADAMTS5, PEDF and autophagy related factors. Immunofluorescence assay was used to mark the expression and localization of ADAMTS5 and PEDF. The neovascularization was detected by tube formation test. Our results revealed that ADAMTS5 expression was increased in the vitreous humor of PDR patients and oxygen-induced retinopathy (OIR) mice retinas. Inhibiting ADAMTS5 alleviated pathological angiogenesis and upregulated PEDF expression in the OIR mice. In addition, ADAMTS5 inhibited PEDF secretion in ARPE-19 cells in vitro studies, thereby inhibiting the migration of HMEC-1. Mechanically, ADAMTS5 promoted the autophagic degradation of PEDF. Collectively, inhibition of ADAMTS5 during OIR suppresses pathological angiogenesis. Our study provides a new approach for resolving pathological angiogenesis in PDR.

Diabetic retinopathy and its relation to serum brain-derived neurotrophic factor level

Diabetes mellitus (DM) is a metabolic disorder of the proteins, lipids, and carbohydrates, results in hyperglycemia. Abnormalities in the function of insulin on target cells, its release from beta cells, or both may contribute to DM. The purpose of this research was to assess the progression of diabetic retinopathy (DR) to the levels of serum brain-derived neurotrophic factor (BDNF), glycated hemoglobin (HbA1c), and biochemical parameters. The study included 44 normal control subjects, 44 diabetic participants, who were separated into four groups based on their diabetes status and the results of fundoscopic examination. A commercial enzyme-linked immunosorbent assay kit was used to measure the levels of BDNF in the serum. The analysis revealed that diabetics had significantly lower serum BDNF levels than non-diabetics (p&lt; 0.001). Also, there was a significant reduction in BDNF levels with the development of proliferative diabetic retinopathy in comparison with diabetics without DR (p &lt; 0.001). In conclusion, serum BDNF levels decreased significantly in diabetics with and without DR compared to apparently healthy individuals, as well as with the progression of DR.

Integration of Vitreous Lipidomics and Metabolomics for Comprehensive Understanding of the Pathogenesis of Proliferative Diabetic Retinopathy.

As a vision-threatening complication of diabetes mellitus (DM), proliferative diabetic retinopathy (PDR) is associated with sustained metabolic disorders. Herein, we collected the vitreous cavity fluid of 49 patients with PDR and 23 control subjects without DM for metabolomics and lipidomics analyses. Multivariate statistical methods were performed to explore relationships between samples. For each group of metabolites, gene set variation analysis scores were generated, and we constructed a lipid network by using weighted gene co-expression network analysis. The association between lipid co-expression modules and metabolite set scores was investigated using the two-way orthogonal partial least squares (O2PLS) model. A total of 390 lipids and 314 metabolites were identified. Multivariate statistical analysis revealed significant vitreous metabolic and lipid differences between PDR and controls. Pathway analysis showed that 8 metabolic processes might be associated with the development of PDR, and 14 lipid species were found to be altered in PDR patients. Combining metabolomics and lipidomics, we identified fatty acid desaturase 2 (FADS2) as an important potential contributor to the pathogenesis of PDR. Collectively, this study integrates vitreous metabolomics and lipidomics to comprehensively unravel metabolic dysregulation and identifies genetic variants associated with altered lipid species in the mechanistic pathways for PDR.

Prognostic factors for the development and progression of proliferative diabetic retinopathy in people with diabetic retinopathy.

Prognostic factors for the development and progression of proliferative diabetic retinopathy in people with diabetic retinopathy.

Low risk for diabetic complications in type 1 diabetes patients carrying a protective insulin gene variant.

Type 1 diabetes patients carrying a 'protective' insulin gene (INS) variant present a disease endotype with reduced insulin antibody titers, preserved beta cell function and improved glycemic control. We tested whether this protective INS variant associated with lowered risk for development of proliferative diabetic retinopathy (PDR) and diabetic kidney disease (DKD) as long-term diabetic complications. Insulin gene polymorphisms were evaluated in 1,363 type 1 diabetes patients participating in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study that compared intensive versus conventional insulin therapy in relation with development of PDR and DKD with a follow-up of over two decades. PDR and DKD were absent in type 1 diabetes patients carrying the protective INS variant and receiving intensive insulin therapy (the current standard of clinical care) 1-5 years from their diagnosis (n = 67; mean post-diagnosis follow up of 20.4 ± 1.6 years), versus 11 of 258 patients (4.3%) lacking this variant (20.4 ± 1.8 years follow up). In the secondary intervention group of the intensive therapy arm (1-15 years of disease), PDR was significantly less frequent in carriers of the protective INS variant than those without it (4 of 83 [4.8%] vs. 31 of 260 [11.9%]; p = 0.032; 26.1 ± 3.9 and 26.3 ± 4.1 years follow-up, respectively), whereas DKD frequencies were no different between those with or without this variant (5 of 83 [6.0%] vs. 11 of 260 [4.2%]). Carrying a copy of this protective INS variant further reduces the risk of diabetic complications achieved by intensive insulin therapy and marks a disease endotype with superior glycemic control, increased and extended beta cell function, and prevention of DKD and PDR.

Increased Angiopoietin-1 and -2 levels in human vitreous are associated with proliferative diabetic retinopathy.

Diabetic retinopathy is a frequent complication of diabetes mellitus and a leading cause of blindness in adults. The objective of this study was to elucidate the diabetic retinopathy pathophysiology in more detail by comparing protein alterations in human vitreous of different diabetic retinopathy stages. Vitreous samples were obtained from 116 patients undergoing pars plana vitrectomy. Quantitative immunoassays were performed of angiogenic factors (VEGF-A, PIGF, Angiopoietin-1, Angiopoietin-2, Galectin-1) as well as cytokines (IL-1β, IL-8, IFN-γ, TNF-α, CCL3) in samples from control patients (patients who don't suffer from diabetes; n = 58) as well as diabetes mellitus patients without retinopathy (n = 25), non-proliferative diabetic retinopathy (n = 12), and proliferative diabetic retinopathy patients (n = 21). In addition, correlation analysis of protein levels in vitreous samples and fasting glucose values of these patients as well as correlation analyses of protein levels and VEGF-A were performed. We detected up-regulated levels of VEGF-A (p = 0.001), PIGF (p<0.001), Angiopoietin-1 (p = 0.005), Angiopoietin-2 (p<0.001), IL-1β (p = 0.012), and IL-8 (p = 0.018) in proliferative diabetic retinopathy samples. Interestingly, we found a strong positive correlation between Angiopoietin-2 and VEGF-A levels as well as a positive correlation between Angiopoietin-1 and VEGF-A. This indicated that further angiogenic factors, besides VEGF, but also pro-inflammatory cytokines are involved in disease progression and development of proliferative diabetic retinopathy. In contrast, factors other than angiogenic factors seem to play a crucial role in non-proliferative diabetic retinopathy development. A detailed breakdown of the pathophysiology contributes to future detection and treatment of the disease.

The Relationship Between AKR1B1 rs759853 (C-106T) Polymorphism and the Diabetic Retinopathy Severity in Turkish Type 2 Diabetes Mellitus Patients

Aim: Diabetes mellitus (DM) is an important health problem with an increasing incidence worldwide and causes many complications. Diabetic retinopathy (DR) is one of the most serious complications of DM. Polymorphisms of the AKR1B1 gene, which encodes an aldose reductase enzyme, have been associated with development of DM and DR in some studies. The current study aims to investigate the relationship of AKR1B1 rs759853 polymorphism with type 2 DM (T2DM), DR and DR severity in the Turkish population. Materials and Methods: A total of 437 individuals, including 141 T2DM patients without DR, 125 T2DM patients with DR, and 171 healthy controls, were included in the study. Genotyping was performed using PCR-RFLP method.Results: An association between T allele / TT genotype and increased risk of proliferative diabetic retinopathy (PDR) was detected. In the logistic regression analysis in which other risk factors were included, rs759853 polymorphism and diabetes duration were found to be associated with the PDR development. There was no significant relationship between the AKR1B1 rs759853 variation and the development of T2DM and DR. Conclusion: Obtained data showed that AKR1B1 rs759853 polymorphism is not associated with the development of T2DM and DR in the Turkish patients, but TT genotype and diabetes duration are independent risk factors for the development of PDR.

Association of Proliferative Diabetic Retinopathy in the Elderly with the Blood Complement System

A common complication of diabetes mellitus, mainly type 2, is diabetic retinopathy, among which the most unfavorable form for complete loss of vision is considered to be proliferative diabetic retinopathy. The participation of the complement system in the development of proliferative diabetic retinopathy is mainly devoted to experimental work on a limited number of blood complement components and without assessing their risk in the pathogenesis of the disease. The purpose of the study was to determine the association of components of the blood serum complement system with the development of proliferative diabetic retinopathy in the elderly. In clinical conditions, 115 patients 60–74 years old suffering from proliferative diabetic retinopathy and 48 patients of the same age with the absence of this ophthalmopathology were examined. The components of the blood complement system were studied by enzyme immunoassay and hemolytic method. The relative risk of the influence of the complement components was calculated according to the generally accepted method. There was a statistically significant increase in the blood serum of patients with proliferative diabetic retinopathy of most components of the complement system, with the exception of the C1 ing. and C5 components. The content of the C3a component increased especially to 127.6 ± 4.7 ng / ml versus 30.4 ± 3.5 ng/ml in the control, the C5a component to 5.6 ± 0.5 ng/ml versus 2.4 ± 0.3 ng/ml, and factor H to 228.7 ± 4.9 versus 106.3 ± 3.8 mng / ml, respectively. The highest value of the relative risk among the studied components is inherent in the C3a component of the blood complement with a reliable confidence interval of 4,451–5,103. The development of proliferative diabetic retinopathy in the elderly is associated with an increased content of C3a, C5a components and factor H in the blood serum, which can be used to develop targeted therapy for this disease.

Keeping an eye on the diabetic foot: The connection between diabetic eye disease and wound healing in the lower extremity.

Diabetic eye disease is strongly associated with the development of diabetic foot ulcers (DFUs). DFUs are a common and significant complication of diabetes mellitus (DM) that arise from a combination of micro- and macrovascular compromise. Hyperglycemia and associated metabolic dysfunction in DM lead to impaired wound healing, immune dysregulation, peripheral vascular disease, and diabetic neuropathy that predisposes the lower extremities to repetitive injury and progressive tissue damage that may ultimately necessitate amputation. Diabetic retinopathy (DR) is caused by cumulative damage to the retinal mic-rovasculature from hyperglycemia and other diabetes-associated factors. The severity of DR is closely associated with the development of DFUs and the need for lower extremity revascularization procedures and/or amputation. Like the lower extremity, the eye may also suffer end-organ damage from macrovascular compromise in the form of cranial neuropathies that impair its motility, cause optic neuropathy, or result in partial or complete blindness. Additionally, poor perfusion of the eye can cause ischemic retinopathy leading to the development of proliferative diabetic retinopathy or neovascular glaucoma, both serious, vision-threatening conditions. Finally, diabetic corneal ulcers and DFUs share many aspects of impaired wound healing resulting from neurovascular, sensory, and immunologic compromise. Notably, alterations in serum biomarkers, such as hemoglobin A1c, ceruloplasmin, creatinine, low-density lipoprotein, and high-density lipoprotein, are associated with both DR and DFUs. Monitoring these parameters can aid in prognosticating long-term outcomes and shed light on shared pathogenic mechanisms that lead to end-organ damage. The frequent co-occurrence of diabetic eye and foot problems mandate that patients affected by either condition undergo reciprocal comprehensive eye and foot evaluations in addition to optimizing diabetes management.

Bie-Jia-Ruan-Mai-Tang, a Chinese Medicine Formula, Inhibits Retinal Neovascularization in Diabetic Mice Through Inducing the Apoptosis of Retinal Vascular Endothelial Cells.

Proliferative diabetic retinopathy (PDR) is one of the main complications of diabetes, mainly caused by the aberrant proliferation of retinal vascular endothelial cells and the formation of new blood vessels. Traditional Chinese medicines possess great potential in the prevention and treatment of PDR. Bie-Jia-Ruan-Mai-Tang (BJ), a Chinese medicine formula, has a good therapeutic effect on PDR clinically; however, the mechanism of action involved remains unclear. Therefore, we investigated the effect of BJ on PDR through in vitro and in vivo experiments. A diabetic mouse model with PDR was established by feeding a high-fat–high-glucose diet combined with an intraperitoneal injection of streptozotocin (STZ), while high-glucose-exposed human retinal capillary endothelial cells (HRCECs) were employed to mimic PDR in vitro. The in vivo experiments indicated that BJ inhibited the formation of acellular capillaries, decreased the expression of VEGF, and increased the level of ZO-1 in diabetic mice retina. In vitro experiments showed that high glucose significantly promoted cell viability and proliferation. However, BJ inhibited cell proliferation by cycle arrest in the S phase, thus leading to apoptosis; it also increased the production of ROS, decreased the mitochondrial membrane potential, reduced the ATP production, and also reduced the expressions of p-PI3K, p-AKT, and Bcl-xL, but increased the expressions of Bax and p-NF-κB. These results suggest that BJ induces the apoptosis of HRCECs exposed to high glucose through activating the mitochondrial death pathway by decreasing the PI3K/AKT signaling and increasing the NF-κB signaling to inhibit the formation of acellular capillaries in the retina, thus impeding the development of PDR.

Changes in aqueous and vitreous inflammatory cytokine levels in proliferative diabetic retinopathy: a systematic review and meta-analysis.

Diabetic retinopathy is a major complication of diabetes mellitus, where in its most advanced form ischemic changes lead to the development of retinal neovascularization, termed proliferative diabetic retinopathy (PDR). While the development of PDR is often associated with angiogenic and inflammatory cytokines, studies differ on which cytokines are implicated in disease pathogenesis and on the strength of these associations. We therefore conducted a systematic review and meta-analysis to quantitatively assess the existing body of data on intraocular cytokines as biomarkers in PDR. A comprehensive search of the literature without year limitation was conducted to January 18, 2021, which identified 341 studies assessing vitreous or aqueous cytokine levels in PDR, accounting for 10379 eyes with PDR and 6269 eyes from healthy controls. Effect sizes were calculated as standardized mean differences (SMD) of cytokine concentrations between PDR and control patients. Concentrations (SMD, 95% confidence interval, and p-value) of aqueous IL-1β, IL-6, IL-8, MCP-1, TNF-α, and VEGF, and vitreous IL-2, IL-4, IL-6, IL-8, angiopoietin-2, eotaxin, erythropoietin, GM-CSF, GRO, HMGB-1, IFN-γ, IGF, IP-10, MCP-1, MIP-1, MMP-9, PDGF-AA, PlGF, sCD40L, SDF-1, sICAM-1, sVEGFR, TIMP, TNF-α, and VEGF were significantly higher in patients with PDR when compared to healthy nondiabetic controls. For all other cytokines no differences, failed sensitivity analyses or insufficient data were found. This extensive list of cytokines speaks to the complexity of PDR pathogenesis, and informs future investigations into disease pathogenesis, prognosis, and management.

Exploring the Immune Infiltration Landscape and M2 Macrophage-Related Biomarkers of Proliferative Diabetic Retinopathy.

BackgroundsDiabetic retinopathy (DR), especially proliferative diabetic retinopathy (PDR), is the major cause of irreversible blindness in the working-age population. Increasing evidence indicates that immune cells and the inflammatory microenvironment play an important role during PDR development. Herein, we aim to explore the immune landscape of PDR and then identify potential biomarkers correlated with specific infiltrating immune cells.MethodsWe mined and re-analyzed PDR-related datasets from the Gene Expression Omnibus (GEO) database. Using the cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithm, we investigated the infiltration of 22 types of immune cells in all selected samples; analyses of differences and correlations between infiltrating cells were used to reveal the immune landscape of PDR. Thereafter, weighted gene co-expression network analysis (WGCNA) and differential expression analysis were applied to identify the hub genes on M2 macrophages that may affect PDR progression.ResultsSignificant differences were found between infiltration levels of immune cells in fibrovascular membranes (FVMs) from PDR and normal retinas. The percentages of follicular helper T cells, M1 macrophages, and M2 macrophages were increased significantly in FVMs. Integrative analysis combining the differential expression and co-expression revealed the M2 macrophage-related hub genes in PDR. Among these, COL5A2, CALD1, COL6A3, CORO1C, and CALU showed increased expression in FVM and may be potential biomarkers for PDR.ConclusionsOur findings provide novel insights into the immune mechanisms involved in PDR. COL5A2, CALD1, COL6A3, CORO1C, and CALU are M2 macrophage-related biomarkers, further study of these genes could inform novel ideas and basis for the understanding of disease progression and targeted treatment of PDR.

Statin use and the risk of progression to vision threatening diabetic retinopathy.

This study aims to assess the effect of statins on progression from nonproliferative diabetic retinopathy (NPDR) to vision-threatening diabetic retinopathy (VTDR), proliferative diabetic retinopathy (PDR) or diabetic macular edema (DME). Two cohort studies using a U.S. medical claims database from 2002 to 2019 including NPDR patients 18 years or older. A risk factor analysis performed a time-updating cox regression model assessing statin usage. A second new-user active comparator design analysis replicating a previously published study. Main outcomes included a new diagnosis of VTDR (composite of either PDR or DME) or DME and PDR individually for the risk factor study and included additional outcomes of new DR, NPDR, vitreous hemorrhage (VH) and tractional retinal detachment (TRD) for the new user study. Risk factor analysis included 66 617 statin users with NPDR at baseline and 83 365 nonstatin users. Of these, 27 325 (18.2%) progressed to VTDR, 4086 (2.71%) progressed to PDR, and 22 750 (15.1%) progressed to DME. After multivariable analysis, no protective effect of statin use was found for progression to VTDR, PDR, or DME (HR=1.01-3, p >0.33 for all comparisons). Replicated new user design analysis also showed no protective effect for statins on risk of development of DR (HR=1.03, 95% CI: 0.99-1.07, p=0.13), PDR (HR=0.89, 95% CI: 0.79-1.02, p=0.09), DME (HR=0.94, 95% CI: 0.86-1.03, p=0.21), VH (HR=1.00, 95% CI: 0.86-1.16, p=0.99), and TRD (HR=1.11, 95% CI: 0.89-1.38, p=0.36). Statin use was found not to be protective for progression of DR regardless of study methodology. These results suggest that the specifics of the population studied rather than differing study methodology are important in assessing the effect of statins on DR progression.

Axl Is Essential for in-vitro Angiogenesis Induced by Vitreous From Patients With Proliferative Diabetic Retinopathy.

Proliferative diabetic retinopathy (PDR), characterized mainly with abnormal epiretinal angiogenesis forming fibrovascular membranes (FVMs), threatens vision of people with diabetes; FVMs consist of extracellular matrix and a variety of cell types including vascular endothelial cells. Axl, one of receptor tyrosine kinases, can be activated indirectly by vascular endothelial growth factor-A (VEGF-A) via an intracellular route for promoting angiogenesis. In this study, we revealed that growth arrest-specific protein 6 (Gas6), a specific ligand of Axl, was elevated in vitreous from patients with PDR and that Axl was activated in FVMs from patients with PDR. In addition, we demonstrated that in cultured human retinal microvascular endothelial cells (HRECs), Axl inhibition via suppression of Axl expression with Clustered Regularly Interspaced Short Palindromic Repeats/ CRISPR-associated protein 9 or through inactivation with its specific inhibitor R428 blocked PDR vitreous-induced Akt activation and proliferation of HRECs. Furthermore, PDR vitreous-heightened migration and tube formation of HRECs were also blunted by restraining Axl. These results indicate that in the pathogenesis of PDR, Axl can be activated by Gas6 binding directly and by VEGF-A via an intracellular route indirectly, suggesting that Axl plays a pivotal role in the development of PDR and that Axl inhibition shows a bright promise for PDR therapy.

Chemerin/CMKLR1 Axis Promotes the Progression of Proliferative Diabetic Retinopathy.

Background Diabetic retinopathy (DR) is a prevalent microvascular complication of diabetes, and the levels of chemerin were associated with the severity of DR. However, there is no research on chemerin in the development of proliferative diabetic retinopathy (PDR). Therefore, our study aimed to explore the relationship between chemerin and PDR. Methods The levels of chemerin/chemokine-like receptor (CMKLR1), proinflammatory cytokines, and vascular endothelial growth factor (VEGF) in 90 cases of PDR and nonproliferative diabetic retinopathy (NPDR) patients and in high glucose (HG) stimulated human retinal pigment epithelium cells (ARPE-19) were evaluated by ELISA. Moreover, chemerin was added into HG-induced ARPE-19 cells to assess its effect on proinflammatory cytokines and VEGF. Results The levels of chemerin/CMKLR1 were higher in PDR patients than NPDR ones, and chemerin was positively correlated with CMKLR1 in PDR patients. Compared to NPDR, the secretions of proinflammatory cytokines and VEGF were increased in PDR patients and positively correlated with chemerin/CMKLR1. Additionally, chemerin activated CMKLR1 and aggravated HG-induced cell injury, inflammatory responses, and VEGF expressions in ARPE-19 cells. Conclusion Our study demonstrated that chemerin/CMKLR1 axis aggravated the progression of PDR, which suggested that inhibition of chemerin might serve as a new therapeutic approach to treat PDR.

Increasing metabolic variability increases the risk for vitrectomy in proliferative diabetic retinopathy.

Proliferative diabetic retinopathy (PDR) can be treated by retinal photocoagulation, but in some cases, the treatment is initiated too late or is insufficient so that the disease advances to a stage requiring vitrectomy. There is a need to identify risk factors that can predict if patients with PDR will develop complications in need for vitrectomy. Survival analysis with death as competing risk was used to study systemic risk factors for PDR progression to a complication in need for vitrectomy in right eyes of all 1288 diabetic patients from the Aarhus area, Denmark, who had developed proliferative retinopathy in the right eye during the 25years period from 1 July 1994 until 1 July 2019. The overall cumulative incidence of reaching a vitrectomy end point in the right eye was 24.1% (n = 311). In 9.3% (n = 120) of the patients where vitrectomy had been performed together with the first photocoagulation, the age of onset of diabetes was significantly higher (p < 0.0001), the diabetes duration longer (p < 0.035) and BMI higher (p < 0.01) than in the patients who had been vitrectomized later than the first photocoagulation. The risk for vitrectomy was significantly increased by high variability of HbA1c before the development of PDR (p < 0.0001), but not by other parameters known to increase the risk for developing PDR. Increasing variability of HbA1c before the development of PDR increases the risk for progression to a complication in need of vitrectomy. The need for vitrectomy is unaffected by other risk factors known to increase the risk for developing PDR.

RISK FACTORS FOR THE OCCURRENCE OF PRIMARY OPEN-ANGLE GLAUCOMA IN PATIENTS WITH DIABETIC RETINOPATHY AND TYPE 2 DIABETES

The aim of this work was to identify risk factors for the occurrence of primary open-angle glaucoma in patients with diabetic retinopathy and type 2 diabetes mellitus by conducting a regression analysis of the mutual influence of these diseases. We examined 649 patients (649 eyes), among whom 301 patients (301 eyes) had diabetic retinopathy and glaucoma; 164 patients (164 eyes) had diabetic retinopathy only; 81 patients (81 eyes) had only glaucoma and 103 patients (103 eyes) did not have these diseases (control). The construction of logistic regression models was carried out in the GLZ module of the Statistica 10 software (StatSoft, Inc. USA). It was found that the development of primary open-angle glaucoma directly depended on the duration of diabetes and the intraocular pressure level, and vice versa — on visual acuity (p &lt; 0.001). The development of diabetic retinopathy did not depend on the presence of glaucoma, but it was directly dependent on the blood content of glucose and glycated hemoglobin. Men had a lower risk of developing diabetic retinopathy than women(OR = 0.800; 95% CI 0.76-0.84). Also, men had a lower risk of glaucoma (OR = 0.95; 95% CI 0.94–0.96). Stratification by stages of diabetic retinopathy showed the effect of intraocular pressure, decreased visual acuity and glaucoma stages on the development of proliferative diabetic retinopathy (p &lt; 0.001). Increased intraocular pressure was an independent factor in the development of retinopathy. The development of glaucoma of the initial stage was directly influenced by an increase of blood glycated hemoglobin and by the stage of diabetic retinopathy. The occurrence of stage 2 glaucoma was influenced by the duration of diabetes and visual acuity, stage 3 glaucoma — by visual acuity, and stage 4 glaucoma – by the age and duration of diabetes. Independent risk factors for glaucoma were duration of diabetes, increased intraocular pressure, and low visual acuity. When stratified by stage, there was no evidence of a reduction in the risk of developing diabetic retinopathy and glaucoma in men. Thus, the features of the mutual influence of the development of diabetic retinopathy and primary open-angle glaucoma in type 2 diabetes mellitus have been established.