NITRIC-OXIDE AVAILABILITY IN DIABETES-MELLITUS

Diabetes mellitus is associated with early development of cardiovascul ar complications. Under physiological conditions the endothelium prote cts against the development of atherosclerosis. Endothelial cells prod uce, e.g., nitric oxide (NO), a substance which is capable of keeping vascular tone, coagulation and inflammation well balanced. However, in pathological conditions, such as in diabetes mellitus, impaired NO ac tivity may be present. Decreased NO activity can be caused by impaired production of NO, due to uncoupling of receptor-mediated signal trans duction, a deficiency of the NO synthase (NOS) substrate L-arginine, o r a decreased availability of one or more cofactors essential for opti mal functioning of NOS. However, hyperglycaemia also stimulates the pr oduction of advanced glycosylated end products, enhances the polyol pa thway and activates protein kinase C. These conditions may lead to inc reased oxidative stress. Reactive oxygen species rapidly inactivate NO leading to the formation of peroxynitrite. Peroxynitrite is a toxic o xidant capable of damaging many biological molecules. Reduced NO avail ability may not only be of relevance to the development of atheroscler otic complications in diabetes but may also interfere with insulin-med iated postprandial glucose disposal and possibly contribute to the dev elopment of insulin resistance. Understanding of the complex metabolic disturbances interacting with the NO system may provide us with furth er therapeutic options to decrease cardiovascular morbidity and mortal ity in diabetes mellitus. (C) 1998 John Wiley & Sons, Ltd.