Aldose Reductase in the Retina

Aldose reductase (E.C. 1.1.1.21), an intracellular enzyme of polyol pathway, catalyzes NADPHdependent reduction of glucose to sorbitol. Under normoglycemia, most of the cellular glucose is phosphorylated into glucose-6-phosphate by hexokinase. A minor part of non-phosphorylated glucose enters the polyol pathway, the alternate route of glucose metabolism. However, under hyperglycemia, because of saturation of hexokinase with ambient glucose, aldose reductase is activated, leading to excessive production of sorbitol. Intracellular accumulation of sorbitol is thought to result in irreversible damage. In the diabetic eye, the increased sorbitol accumulation in retina has been implicated in the pathogenesis of retinopathy, characterized by pericyte loss, basal membrane thickening, the major ocular complications of diabetes. Nearly all diabetic subjects have the same degree of retinopathy after 20 years of diabetes. 50% of patients with insulin dependent diabetes mellitus have proliferative retinopathy after 15 years. In addition, macular edema frequently produces central vision loss and blindness most commonly in non-insulin dependent diabetes mellitus. Therefore, aldose reductase enzyme inhibition is becoming one of the therapeutic strategies that have been proposed to prevent or ameliorate long-term diabetic complications.