Circulation. 2002;105:576-582
doi: 10.1161/hc0502.103333
doi: 10.1161/hc0502.103333
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(Circulation. 2002;105:576.)
© 2002 American Heart Association, Inc.
Clinical Investigation and Reports |
Insulin Causes Endothelial Dysfunction in Humans
Sites and Mechanisms
From the Division of Endocrinology and Metabolic Diseases (A.C., S.B., M.M., E.B., R.C.B.) and Division of Internal Medicine (G.A., A.L.), Department of Biomedical and Surgical Sciences, University of Verona Medical School and Azienda Ospedaliera di Verona, Verona, Italy.
Correspondence to Riccardo C. Bonadonna, MD, Division of Endocrinology, Ospedale Civile Maggiore, Piazzale Stefani 1, I37126 Verona, Italy. E-mail rcbonado{at}tin.it
Background— Insulin resistance is often accompanied by hyperinsulinemia and may predispose to atherosclerosis. Endothelium plays a central role in atherogenesis. The in vivo effects of hyperinsulinemia on endothelial function of large conduit arteries are unknown.
Methods and Results— Twenty-five healthy subjects were enrolled for study. In study A (n=9), subjects underwent both a time-control saline study and a euglycemic low-dose insulin (insulin 
110 pmol/L) clamp for 6 hours. Study B (n=5) was identical to study A except that the euglycemic clamp was performed at high physiological insulin concentrations (440 pmol/L). In study C (n=7), subjects underwent two 4-hour euglycemic insulin (110 pmol/L) clamps with and without the concomitant infusion of an antioxidant (vitamin C). In study D (n=4), two saline time-control studies were performed with and without the concomitant infusion of vitamin C. In all studies, both at baseline and throughout the experimental period, endothelium-dependent (flow-mediated) and endothelium-independent (nitroglycerin-induced) vasodilation was assessed in femoral and brachial arteries by echo Doppler. Both low (study A) and high physiological (study B) hyperinsulinemia abolished endothelium-dependent vasodilation, whereas endothelium-independent vasodilation was unaffected. Vitamin C fully restored insulin-impaired endothelial function without affecting endothelium-independent vasodilation (study C). Vitamin C had no effects on endothelium-dependent or endothelium-independent vasodilation during saline control studies (study D).
Conclusions— Modest hyperinsulinemia, mimicking fasting hyperinsulinemia of insulin-resistant states, abrogates endothelium-dependent vasodilation in large conduit arteries, probably by increasing oxidant stress. These data may provide a novel pathophysiological basis to the epidemiological link between hyperinsulinemia/insulin-resistance and atherosclerosis in humans.
Key Words: insulin • endothelium • atherosclerosis
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