Hyperglycemia as a cause of diabetic retinopathy

Abstract

Diabetes mellitus is marked by hyperglycemia and a variety of other metabolic disorders. The significance of hyperglycemia in the pathogenesis of diabetic retinopathy has proven difficult to evaluate in patients. Diabetic dogs are known to develop retinal lesions morphologically identical to those typical of diabetes in man, provided hyperglycemia in the animal is allowed to persist at least for many months and usually for 3 to 5 years. The development of retinopathy in this animal model can be inhibited by careful improvement of diabetic (glycemic) control. Comparable retinopathy has recently been found to develop in nondiabetic dogs as a result of experimental galactosemia of several years' duration. Included in this retinopathy and in the retinopathy of diabetic patients and dogs as well are saccular capillary aneurysms, hemorrhages, nonperfused or acellular vessels, varicose vessels, and loss of capillary pericytes. Retinal capillary basement membrane has been measured (to date) in two dogs that had been galactosemic for 5 years, and it was found to be significantly thicker than in normal dogs ( P < 0.01). Many metabolic abnormalities typical of diabetes are absent from galactosemic dogs. Unlike diabetic dogs, the blood levels of glucose, nonesterified fatty acids, branched-chain amino acids, and fibrinogen are not elevated in the galactosemic dogs, and their serum insulin concentration seems normal. Excessive blood hexose itself appears to be an important determinant of retinopathy. One possible mechanism by which excessive blood hexose might produce retinopathy involves the polyol pathway. Retinal microvessels isolated from normal dogs can produce polyol from hexose in vitro, and this polyol-producing activity can be inhibited by the aldose reductase inhibitor sorbinil. Other investigators have recently shown that the thickening of retinal capillary basement membrane that occurs in diabetic rats and galactose-fed rats can be inhibited by treatment with aldose reductase inhibitors. The influence of sorbinil on the development of retinopathy and other microvascular abnormalities is currently being investigated by us in diabetic and galactosemic dog models.