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 complications, macrovascular disease and microangiopathy. Endothelial dysfunction is a consequence of a disturbance in the L-arginine/nitric oxide pathway. Its occurrence 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. Dysglycaemia results in hyperoxidative stress and increased formation of advanced-glycosylation endproducts, both of which enhance the oxidative modification of lipoprotein particles. Based on extensive in vitro studies and on human data, we generate the hypothesis that the development of endothelial dysfunction in NIDDM is a consequence of the effect of dyslipoproteinaemia, in particular increased circulatory concentrations of modified small dense LDL and of hyperoxidative stress on the formation, action and disposal of nitric oxide, by diverse molecular mechanisms; HDL is proposed to have a protective effect on these processes through its enzymic antioxidant properties. The hypothesis proposed is simple, testable and consistent with wide sources of evidence. The practical implications of the hypothesis and the existing opportunities for the prevention and reversal of endothelial dysfunction in NIDDM are also reviewed and discussed.