Perspectives in Diabetes Role of Oxidative Stress in Development of Complications

NC-(carboxymethyl)lysine, N'-(carboxymethyl)hydroxylysine, and the fluorescent cross-link pentosidine are formed by sequential glycation and oxidation reactions between reducing sugars and proteins. These compounds, termed glycoxidation products, accumulate in tissue collagen with age and at an accelerated rate in diabetes. Although glycoxidation products are present in only trace concentrations, even in diabetic collagen, studies on glycation and oxidation of model proteins in vitro suggest that these products are biomarkers of more extensive underlying glycative and oxidative damage to the protein. Possible sources of oxidative stress and damage to proteins in diabetes include free radicals generated by autoxidation reactions of sugars and sugar adducts to protein and by autoxidation of unsaturated lipids in plasma and membrane proteins. The oxidative stress may be amplified by a continuing cycle of metabolic stress, tissue damage, and cell death, leading to increased free radical production and compromised free radical inhibitory and scavenger systems, which further exacerbate the oxidative stress. Structural characterization of the cross-links and other products accumulating in collagen in diabetes is needed to gain a better understanding of the relationship between oxidative stress and the development of complications in diabetes. Such studies may lead to therapeutic approaches for limiting the damage from glycation and oxidation reactions and for complementing existing therapy for treatment of the complications of diabetes. Diabetes 40:405-12, 1991 or decreased efficiency of inhibitory and scavenger systems. The stress then may be amplified and propagated by an autocatalytic cycle of metabolic stress, tissue damage, and cell death, leading to a simultaneous increase in free radical production and compromised inhibitory and scavenger mechanisms, which further exacerbate the oxidative stress. For practical reasons, neither the rate of oxidant production nor the steady-state levels of reactive oxygen species are easily measured in biological systems. Thus, oxidative stress must be inferred from measurements of oxidative damage as estimated from the kinetics of formation, the steady-state levels, or the extent of accumulation of oxidation products in tissues, plasma, or urine. However, the detection of increased levels of oxidation products in tissues is not, per se, sufficient to implicate oxidative stress in the pathology unless the damage can be logically and quantitatively related to the development of pathology and until it can be shown that inhibition of oxidative damage prevents or retards the disease process. The concept I develop in this article is that oxidative stress may be a common pathway linking diverse mechanisms for the pathogenesis of complications in diabetes. Mechanisms that contribute to increased oxidative stress in diabetes may include not only increased nonenzymatic glycosylation (glycation) and autoxidative glycosylation but also metabol~c stress resulting from changes in energy metabolism, alterations in sorbitol pathway activity, changes in the level of inflammatory mediators and the status of antioxidant defense svstems, and localized tissue damaae resultina from ~ V D O X ~ ~ a'nd ischemic reperfusion injury. he goa of this artlck IS to focus more on the common ~athwav the role of ox~dat~ve