Maurice (“Reece”) B Landers III, MD
This brief talk described risk factors for diabetic retinopathy (DR) and diabetic macular edema (DME), and the molecular biology of diabetic microvascular complications (DMC), including DR.
There is clearly a genetic component to DR. In the Diabetes Control and Complications Trial (DCCT), patients with first-degree relatives with DR had a 5.4-fold greater risk of developing severe DR than patients who do not have a family history of DR. The Malmo Preventive Project found a linkage between the development of DR and 3 abnormal genes which increased insulin secretion and decreased insulin sensitivity. Future genetic research may permit individualization of risk factors and interventions to prevent DR or reduce its severity.
Anemia increases the risk of developing DME. Anemia may occur in patients with diabetes who do not have kidney disease.
Recently, 4 major molecular mechanisms for DMC have been proposed. The unifying defect underlying these mechanisms is mitochondrial superoxide overproduction. The 4 mechanisms include increased polyol flux, increased advanced glycation endproduct (AGE) formation, increased protein kinase C (PKC) activation, and increased hexosamine flux.
The polyol pathway is associated with increased production of aldose reductase, leading to increased oxidative stress (a general term describing the steady-state level of oxidative damage by reactive oxygen species [ROS] in a cell, tissue, or organ.) Aldose reductase is primarily present in pericytes, the capillary supporting cells, and not the endothelial cells. This may explain why pericyte loss precedes the development of microaneurysms. Aldose reductase inhibition has been extensively investigated as a target for DMC, but without producing an FDA-approved treatment. Antioxidants also have a theoretical basis as DMC treatments, but this promise has not been realized in clinical trials conducted to date.
AGEs have proinflammatory properties. It has been suggested that AGE formation may explain why diabetes has many characteristics associated with inflammatory disease. AGEs may also decrease vessel elasticity while increasing blood viscosity, damaging the endothelium; this effect may account for the loss of autoregulation of retinal blood flow in diabetic retinopathy.
PKC activation inhibits nitric oxide production (a vasodilator), but increases endothelin-1, vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), plasminogen activator inhibitor-1 (PAI-1), and microvascular matrix protein accumulation. Hyperglycemia increases activation of PKC β and VEGF. Ruboxistaurin, a PKC β inhibitor, received an approvable letter from the Food and Drug Administration earlier this year.
Increased hexosamine flux is associated with increased insulin resistance, TGF-β, and PAI-1. This mechanism has not been investigated as extensively for potential diabetes treatments as the polyol, AGEs, and PKC mechanisms have.
Normoglycemia is necessary but not sufficient to prevent DMC. High blood glucose levels are associated with increased incidence of DMC; reducing blood glucose levels decreases the incidence of diabetic complications. On the other hand, after a period of uncontrolled glycemia, higher rates of DMC occur even after normoglycemia is attained. This puzzling phenomenon is known as hyperglycemic memory. Presently, it is unknown whether the molecular mechanisms underlying DMC independent of hyperglycemia may explain it.
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