Pathophysiological implications of insulin resistance on vascular endothelial function.

BACKGROUND: Insulin resistance is a key component of the insulin resistance syndrome and is a crucially important metabolic abnormality in Type 2 diabetes. Insulin-resistant individuals are at significantly increased risk of cardiovascular disease, although the underlying mechanisms remain incompletely understood. The endothelium is thought to play a critical role in maintaining vascular homeostasis, a process dependent on the balance between the production of nitric oxide, superoxide and other vasoactive substances. Endothelial dysfunction has been demonstrated in insulin-resistant states in animals and humans and may represent an important early event in the development of atherosclerosis. Insulin resistance may be linked to endothelial dysfunction by a number of mechanisms, including disturbances of subcellular signalling pathways common to both insulin action and nitric oxide production. Other potential unifying links include the roles of oxidant stress, endothelin, the renin angiotensin system and the secretion of hormones and cytokines by adipose tissue. Lifestyle measures and drug therapies which improve insulin sensitivity and ameliorate endothelial dysfunction may be important in delaying the progression to overt cardiovascular disease in at risk individuals.
METHODS: We conducted a literature search using Medline, restricted to articles published in the English language between 1966 and the present, and reviewed bibliographies of relevant articles. An initial search strategy employing combinations of the MeSH terms: insulin resistance; endothelium, vascular; insulin; nitric oxide or hyperinsulinaemia produced over 300 references. Focused searches using keywords relevant to the molecular aspects of endothelial function and insulin signalling, and lifestyle or pharmacological interventions relevant to insulin resistance or endothelial function, produced over 300 further references. Abstracts of all references were screened before selecting those relevant to this review.