Mechanisms of oxidative stress in diabetes: Implications for the pathogenesis of vascular disease and antioxidant therapy

Diabetes markedly raises the risk of microvascular and macrovascular disease, the major contributors to higher morbidity and mortality in this increasingly prevalent disorder. Oxidative stress has been postulated as one major contributor to long-term diabetic complications. However, there is considerable controversy regarding the nature, magnitude, and mechanisms of oxidative stress in the diabetic state. Although products of glycoxidation and lipoxidation are elevated in plasma and tissue from humans suffering from diabetes, the exact relationships among hyperglycemia, the diabetic state, and oxidative stress are undetermined. This review focuses on proposed mechanisms for increasing oxidative stress in diabetes, the relationship of oxidant production to hyperglycemia, the contribution of reactive carbonyl compounds that accumulate in the diabetic state to tissue injury, and the potential role of lipids in producing oxidants. Current evidence argues against a generalized increase in oxidative stress in human diabetes, at least in the extracellular milieu. Instead, reactive intermediates generated in certain microenvironments might promote oxidative stress by unique pathways. Thus, many issues need to be addressed, including the suitability of antioxidants for preventing the clinical sequelae of diabetes.