Oxygen metabolism is essential for sustaining aerobic life, and normal cellular homeostasis works on a fine balance between the formation and elimination of reactive oxygen species (ROS). Oxidative stress, a cytopathic consequence of excessive production of ROS and the suppression of ROS removal by antioxidant defense system, is implicated in the development of many diseases, including Alzheimer's disease, and diabetes and its complications. Retinopathy, a debilitating microvascular complication of diabetes, is the leading cause of acquired blindness in developed countries. Many diabetes-induced metabolic abnormalities are implicated in its development, and appear to be influenced by elevated oxidative stress; however the exact mechanism of its development remains elusive. Increased superoxide concentration is considered as a causal link between elevated glucose and the other metabolic abnormalities important in the pathogenesis of diabetic complications. Animal studies have shown that antioxidants have beneficial effects on the development of retinopathy, but the results from very limited clinical trials are somewhat ambiguous. Although antioxidants are being used for other chronic diseases, controlled clinical trials are warranted to investigate potential beneficial effects of antioxidants in the development of retinopathy in diabetic patients.

Antioxidants were administered to diabetic rats and experimentally galactosemic rats to evaluate the ability of these agents to inhibit the development of diabetic retinopathy. Alloxan diabetic rats and nondiabetic rats that were fed 30% galactose randomly received standard diets or the diets supplemented with ascorbic acid and ␣-tocopherol (vitamins C؉E diet) or a more comprehensive mixture of antioxidants (multi-antioxidant diet), including Trolox, ␣-tocopherol, N-acetyl cysteine, ascorbic acid, ␤-carotene, and selenium. Diabetes or galactose feeding of at least 12 months resulted in pericyte loss, acellular capillaries, and basement membrane thickening. Compared with diabetic controls, the development of acellular capillaries was inhibited by 50% (P < 0.05) in diabetic rats that received supplemental vitamins C؉E, and the number of pericyte ghosts tended to be reduced. The vitamins C؉E supplement had no beneficial effect in galactosemic rats, but these rats consumed only approximately half as much of the antioxidants as the diabetic rats. The multi-antioxidant diet significantly inhibited (ϳ55-65%) formation of both pericyte ghosts and acellular capillaries in diabetic rats and galactosemic rats (P < 0.05 vs. controls), without affecting the severity of hyperglycemia. Parameters of retinal oxidative stress, protein kinase C activity, and nitric oxides remained elevated for at least 1 year of hyperglycemia, and these abnormalities were normalized by multi-antioxidant therapy. Thus, longterm administration of antioxidants can inhibit the development of the early stages of diabetic retinopathy, and the mechanism by which this action occurs warrants further investigation. Supplementation with antioxidants can offer an achievable and inexpensive adjunct therapy to help inhibit the development of retinopathy in diabetes. Diabetes 50: 1938 -1942, 2001 H yperglycemia induces metabolic disorders that initiate a sequence of events that lead to the development of retinopathy. This is illustrated convincingly by the evidence that nondiabetic animals in which blood hexose concentration is increased with a galactose-rich diet develop retinal capillary lesions that are indistinguishable from those that develop in diabetic humans or animals (1-4). Multiple hypotheses have proposed how hyperglycemia might cause the development of retinopathy (5-11), but it has been difficult to recognize which abnormalities are critical.Diabetes increases oxidative stress in tissues of both humans and animals, and increased oxidative stress might play a role in the development of diabetic complications (8,(12)(13)(14). Oxidative stress develops in the retina of diabetic animals and galactose-fed animals (9,13,15), indicating that oxidative stress is at least associated with the development of retinopathy. Consistent with this, Armstrong et al. (8) reported a correlation between increased serum lipid hydroperoxides and the prevalence of retinopathy in diabetic patients. Our previous studies showed that dietary supplementation with antioxida...

Retinal mitochondria experience increased oxidative damage in diabetes, and complex III is one of the sources of increased superoxide. MnSOD protects the retina from diabetes-induced abnormalities in the mitochondria and prevents vascular histopathology, strongly implicating the role for MnSOD in the pathogenesis of retinopathy in diabetes.