Pathophysiology Section

Significance Of Research

Diabetic retinopathy is the major cause of new blindness in adults (20 to 74 years old) in the industrialized countries. Whereas the multiple physiological perturbations of diabetes mellitus results from lowered availability and/or cellular recognition of insulin, the complications of diabetes such as diabetic retinopathy, are caused by the chronic hyperglycemia. Although insulin therapy lowers the blood glucose levels enough to preserve life, prudent administration of insulin does not permit complete euglycemia nor prevent the long-term complications of chronic supernormal levels of blood glucose.

Our findings represent experimental animal evidence for the efficacy of a completely novel approach to preventing diabetic complications, which could be used in addition to insulin. The proposed treatment would not involve lowering of blood glucose levels, but instead, it would decrease the toxic effects of hyperglycemia on cells. The earliest effect of elevated glucose levels is a substrate-driven increased flux through the polyol pathway expressed as an increased activity of aldose reductase and concomitant intracellular accumulation of sorbitol, the polyol of glucose. Taking advantage of the fact that aldose reductase has a higher affinity for galactose than for glucose, we were able to induce much higher levels of polyol (galactitol) in the cells of normal rats fed a 50% galactose diet than occurs in diabetic rats or humans. This permitted the creation of a reliable and convenient animal model for diabetic retinopathy. The extremely high level of polyol attained induced sugar cataracts in galactose-fed rats within two weeks, whereas similar cataracts take 2 to 3 months in diabetic rats. All stages of diabetic retinopathy developed within 24 months in galactose-fed rats in contrast to diabetic rats which never show more than the early stages. Four inhibitors of aldose reductase with very different structures (AL-3152, ARI-509, sorbinil, and tolrestat) prevented diabetic-like retinopathy in galactose-fed rats. Such inhibitors should prevent diabetic retinopathy in humans provided they are administered in appropriate dosages and the treatment is started soon after the diagnosis of diabetes.