Possible pathophysiological mechanisms for diabetic angiopathy in type 2 diabetes

The expression of large and small vessel disease in type 2 diabetes differs from that observed in type 1, with a higher prevalence of atherosclerosis and hypertension, maculopathy rather than proliferative retinopathy, and ne phropathy of a more complex nature. Such differences are mirrored by differ ences in vascular pathophysiology with an early impairment of microvascular vasodilatory reserve being a prominent feature. The defect appears to be e ndothelium dependent and in conjunction with evidence of endothelium activa tion suggests that the endothelium plays a crucial role in the pathogenesis of vascular disease in type 2 diabetes and may even be an intrinsic featur e or common antecedent of the insulin resistance syndrome. Several cellular mechanisms may be proposed linking insulin resistance and endothelial dysf unction including (i) abnormalities of common signal transduction mechanism s, (ii) alterations in cell membrane fluidity altering the expression and/o r presentation of a wide range of receptors, or (iii) changes in oxidative stress. It is intuitively unlikely that the alteration of a single signal t ransduction mechanism could be a common cause, particularly as aspects of e ndothelial dysfunction implicate different mechanisms. Accordingly, changes in oxidative stress, either stemming from glucose-mediated increased free- radical generation and/or reduction of antioxidant capacity, are strong con tender mechanisms. Not only may increased oxidative stress result in the qu enching of nitric oxide, neutralizing its many protective functions, but it may also damage DNA, protein structure, and membrane properties. Elucidati ng the links between oxidative stress, endothelial function, and insulin re sistance has important implications for the prevention of diabetic angiopat hy and perhaps for the prevention of diabetes itself. (C) 2000 Elsevier Sci ence Inc. All rights reserved.