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.