GLYCATION, OXIDATION, AND LIPOXIDATION IN THE DEVELOPMENT OF THE COMPLICATIONS OF DIABETES - A CARBONYL STRESS HYPOTHESIS

Modifications of extant plasma proteins, structural proteins,and other macromolecules are enhanced in diabetes because of increased glycatio n (secondary to increased glucose concentrations) and perhaps because of increased oxidative stress, Increased glycation is present from the time of onset of diabetes, but the relation between diabetes and oxid ative stress is less clear: increased oxidative stress may occur later in the course of disease, as vascular damage becomes established, or it may be a feature of uncomplicated diabetes, The combined effects of protein modification by glycation and oxidation may contribute to the development of accelerated atherosclerosis in diabetes and to the dev elopment of microvascular complications, Thus, even if not increased b y diabetes, variations in oxidative stress may modulate the consequenc es of hyperglycemia in individual diabetic patients, In this review, t he close interaction between glycation and oxidative processes is disc ussed, and the theme is developed that the most significant modificati ons of proteins are the result of interactions with reactive carbonyl groups, While glucose itself contains a carbonyl group that is involve d in the initial glycation reaction, the most important and reactive c arbonyls are formed by free radical-oxidation reactions damaging eithe r carbohydrates (including glucose itself) or lipids, The resulting ca rbonyl-containing intermediate products then modify proteins, yielding ''glycoxidation'' and ''lipoxidation'' products, respectively, This c ommon pathway for glucose and lipid-mediated stress, which may contrib ute to diabetic complications, is the basis for the carbonyl stress hy pothesis for the development of diabetic complications.