Diabetic retinopathy (DR) remains a major complication of diabetes and the leading cause of blindness among adults worldwide. DR is a progressive disease affecting both type I and type II diabetic patients at any stage of the disease, and targets the macrovascular and microvascular systems of the retina. DR results from multiple biochemical, molecular and pathophysiological changes to the retinal vasculature which affect both microcirculatory functions and ultimately photoreceptor function. Several neural, endothelial and support cell (pericytes, glia) mechanisms are altered in a pathological fashion in the hyperglycemic environment during diabetes which can disturb important cell surface components in the vasculature producing …show more content…
At some point, injury reaches a point of ‘no return’ where DR will become inevitable. Most of the current therapies are aimed at managing the symptoms of diabetes, or glucose levels. For type I diabetes, the standard treatment is insulin, while for type II diabetes it can be one or a combination of sulfonylureas, thiazolidinediones, biguanides, alpha-glucosidase inhibitors, meglitinides, and insulin (9). However, these drugs do not for the most part treat the underlying microvascular mechanisms contributing to DR. Studies have indicated that despite tight glycemic control, retinal microvascular complications will continue to develop and the factors leading to these complications will persist in DR (10-12). This phenomenon has been termed ‘metabolic memory’ (13-15), where hyperglycemic vascular stresses continue even after the normalization of blood glucose levels. Many factors have been attributed to this phenomenon, such as advanced glycation end products (16), mitochondrial damage and oxidative stress (17), and epigenetic changes (7, 18, 19), all of which will be discussed in detail later in the …show more content…
Several factors are known to increase the risk of developing DR. These include the duration of diabetes, poor glycemic control, high blood pressure, high cholesterol, pregnancy, elevated glycated hemoglobin-A1c (HbA1c) and tobacco use (2). In addition, there are many molecular players that contribute to the development of DR and can be considered as a risk factor in its pathogenesis. These factors include elevated levels of Th1 cytokines and growth factors, which are elevated even prior to evidence of clinical manifestations of DR. Many of these factors (for example, VEGF) drive proliferation, but also lead to a loss of vascular integrity in proliferative DR. Moreover, connective tissue growth factor (CTGF, CCN2) plays a major role in the formation of fibrous tissue around the microvessels, which leads to retinal detachment and tearing (21). In addition, a recent study has shown a correlation between proliferative DR development and plasma erythropoietin (EPO), which was significantly increased (22, 23). This result came to light after reports that DR deterioration accelerates after patients start hemodialysis, and the recent identification of EPO as an angiogenic factor independent of VEGF (23,