Insulin resistance, metabolic syndrome and vascular diseases: update on mechanistic linkages.
Epidemiological associations are now well-established between insulin resistance, the metabolic syndrome and worsened cardiovascular outcomes. A direct role of insulin in vascular biology is also now broadly recognized. Specifically, insulin can directly stimulate the action of nitric oxide synthase, an effect that can be demonstrated both in vitro and in vivo. Insulin resistance, whether present endogenously or produced experimentally through exposure to fatty acids, glucosamine or tumour necrosis factor alpha, is associated with impaired endothelium-dependent vasodilation and, specifically, with impaired insulin-stimulated vasodilation. A number of potential molecular explanations for these observations are being pursued, with evidence to support a number of concurrent pathogenic mechanisms. These include insulin resistance-associated reductions in nitric oxide availability due to increases in oxidative stress (not requiring the presence of hyperglycemia), reduced availability of tetrahydrobiopterin and excess levels of asymmetrical dimethylarginine. A strong body of evidence also supports an excess of the vasoconstrictor endothelin, which may result directly from hyperinsulinemia and/or indirectly due to a loss of the suppressive effects of nitric oxide on endothelin production and action. The current leading edge of investigations into the association between insulin-resistant states and vascular dysfunction involves the expanding repertoire of adipocyte-derived hormones. Of these, particular interest has been focused on adiponectin, which has both vascular and metabolic actions, and may contribute importantly to the connection between metabolism and vascular function. Progress along these novel lines of investigation will continue to expand the understanding of the mechanisms linking insulin resistance, the metabolic syndrome and vascular disease.
Indiana University School of Medicine, Indianapolis, Indiana, USA.
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D000818:Animals; D002318:Cardiovascular Diseases / Q000453:epidemiology* / Q000503:physiopathology; D015897:Comorbidity; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D006801:Humans; D015994:Incidence; D007333:Insulin Resistance; D008297:Male; D024821:Metabolic Syndrome / Q000453:epidemiology* / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism*; D011379:Prognosis; D051381:Rats; D018570:Risk Assessment; D017678:Sex Distribution; D016019:Survival Analysis
D009569:Nitric Oxide