Dysregulated Serum Lipid Metabolism Promotes the Occurrence and Development of Diabetic Retinopathy Associated With Upregulated Circulating Levels of VEGF-A, VEGF-D, and PlGF

Abstract

Purpose: This study aims to explore the correlations of arteriosclerosis-associated plasma indices with various severity levels of diabetic retinopathy (DR) and to test the hypothesis that elevated circulating level of known angiogenic cytokines induced by hyperglycemia is associated with dyslipidemia on DR.Methods: This cross-sectional study consists of 131 patients with type 2 diabetes. The patients were categorized based on their DR status into those with no DR (diabetes mellitus, DM), non-proliferative diabetic retinopathy (NPDR), and proliferative diabetic retinopathy (PDR) groups. The biochemical profile including fasting glucose, glycated hemoglobin (HbA1c), lipid profile were estimated, plasma angiogenic cytokines (vascular endothelial growth factor, VEGF-A, -C, -D) and placental growth factor (PlGF) were analyzed by protein microarrays. The atherogenic plasma index (API) was defined as low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (LDL-C/HDL-C); atherogenic index (AI) was calculated as (TC-(HDL-C))/HDL-C and atherogenic index of plasma (AIP) was defined as log (TG/HDL-C).Results: No significant differences were detected in the duration of hypertension, age, and gender between the three groups. Serum TC and LDL-C, AI, and API in the NPDR group and PDR group were significantly higher than those in the DM group. The circulating level of PlGF, VEGF-A, and VEGF-C were significantly correlated with the severity of DR. VEGF-D is a risk factor independent of API (Z = −2.61, P = 0.009) and AI (Z = −2.40, P = 0.016). Multivariate logistic regression showed that AI and API are strong risk factors for the occurrence and severity of DR. Associated with AI and API, VEGF-D and PlGF contribute to DR: VEGF-D [AI: P = 0.038, odd ratio (OR) = 1.38; VEGF-D: P = 0.002, OR = 1.00. API: P = 0.027, OR = 1.56, VEGF-D:P = 0.002, OR = 1.00] and PlGF [AI: P = 0.021, OR = 1.43; VEGF-D: P = 0.004, OR = 1.50. API: P = 0.011, OR = 1.66; VEGF-D: P = 0.005, OR = 1.49].Conclusions: Total cholesterol (TC) and LDL-C are risk factors for presence of any DR. Atherogenic index and API are novel and better predictive indicators for the occurrence and severity of DR in comparion with the traditional lipid profiles. Abnormal lipid metabolism are associated with the upregulation of circulating cytokines that are linked to the severity of DR.

A Mechanistic Exploratory Study on the Therapeutic Efficacy of Astragaloside IV Against Diabetic Retinopathy Revealed by Network Pharmacology

“…VEGFA is not only the most important inducer of vascular leakage, but also a key angiogenic factor ( Sharma, 2020 ). In a previous study, vegfa-flk-1 signaling has been shown to be the main mediator of endothelial cell mitosis, survival and microvascular permeability ( Zhang, et al, 2021 ), suggesting that VEGF can become an important target for the treatment of ocular diseases. Inhibition of HIF-1α in DR can reduce VEGF expression and inhibit neovascularization in vivo .…”

Plasma Apolipoproteins Predicting the Occurrence and Severity of Diabetic Retinopathy in Patients With Type 2 Diabetes Mellitus

“…The inclusion criteria were described previously (16). The exclusion criteria were the following: coexistence of other retinal diseases including retinal vein occlusion, macular hole, macular pucker, age-related macular degeneration, and inherited retinal diseases; recent history of eye anterior or posterior segment surgery; ocular media opacity; and inability to tolerate examinations due to severe system diseases; patients on lipidlowering therapy or with history of lipid disorders were also excluded (16). Subjects with cardiovascular diseases including angina and stroke as well as other server system disorders were also excluded.…”

“…apoB/ apoA-I 2.7 (AUC: 0.60, sensitivity = 0.50, specificity = 0.6). API 2.24 (AUC: 0.75; sensitivity = 0.71, specificity = 0.52), AI 2.91 (AUC, 0.72; sensitivity = 0.63; specificity = 0.72), AIP (AUC 0.564; sensitivity = 0.607, specificity = 0.552) were selected as the cutoff value as we described previously (16).…”

“…We have previously shown that arteriosclerosis-associated plasma parameters, atherogenic plasma index (API; LDL-C/ HDL-C), atherogenic index (AI; TC-(HDL-C)/HDL-C), atherogenic index of plasma [AIP; Log (TG/HDL-C)] are novel biomarkers and more sensors for the occurrence and progression of DR (16), which provided new insights into the treatment of DR. In comparison with the traditional lipid profiles, a number of studies have confirmed that these indices are more sensitive in predicting the progression of diabetes and DR.…”

Differentially Regulated Apolipoproteins and Lipid Profiles as Novel Biomarkers for Polypoidal Choroidal Vasculopathy and Neovascular Age-Related Macular Degeneration

“…The differential regulation mechanism and the interactions between apos and lipid profiles remain uncertain. Our previous studies have shown that abnormal plasma levels of apolipoproteins and lipid profiles are correlated with variety of retinal vascular disorders including diabetic retinopathy (17)(18)(19). It is interesting to determine if apolipoprotein-mediated differential regulation of lipid metabolism is a pathological cause of the clinical phenotypes of nAMD and PCV.…”