Dyslipoproteinaemia and hyperoxidative stress in the pathogenesis of endothelial dysfunction in non-insulin dependent diabetes mellitus: an hypothesis

Endothelial dysfunction in non-insulin dependent (Type 2) diabetes mellitus (NIDDM) has implications for the pathogenesis of the two major complicatio ns, macrovascular disease and microangiopathy. Endothelial dysfunction is a consequence of a disturbance in the L-arginine/nitric oxide pathway. Its o ccurrence in NIDDM is well supported by both in vitro and in vivo studies. NIDDM results in diverse abnormalities in lipoprotein metabolism, the most significant being hypertriglyceridaemia which is associated with increased plasma concentrations of small dense LDL and low levels of HDL. Dysglycaemi a results in hyperoxidative stress and increased formation of advanced-glyc osylation endproducts, both of which enhance the oxidative modification of lipoprotein particles. Based on extensive in vitro studies and on human dat a, we generate the hypothesis that the development of endothelial dysfuncti on in NIDDM is a consequence of the effect of dyslipoproteinaemia, in parti cular increased circulatory concentrations of modified small dense LDL and of hyperoxidative stress on the formation, action and disposal of nitric ox ide, by diverse molecular mechanisms; HDL is proposed to have a protective effect on these processes through its enzymic antioxidant properties. The h ypothesis proposed is simple, testable and consistent with wide sources of evidence. The practical implications of the hypothesis and the existing opp ortunities for the prevention and reversal of endothelial dysfunction in NI DDM are also reviewed and discussed. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.