Insulin causes endothelial dysfunction in humans: sites and mechanisms.
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.


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 approximately 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 (approximately 440 pmol/L). In study C (n=7), subjects underwent two 4-hour euglycemic insulin (approximately 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.
Arcaro
Guido
G
Division of Endocrinology, Department of Biomedical and Surgical Sciences, University of Verona Medical School and Azienda Ospedaliera di Verona, Verona, Italy.
Cretti
Anna
A
Balzano
Sara
S
Lechi
Alessandro
A
Muggeo
Michele
M
Bonora
Enzo
E
Bonadonna
Riccardo C
RC
D000328:Adult; D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D001916:Brachial Artery / Q000187:drug effects / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology*; D005260:Female; D005263:Femoral Artery / Q000187:drug effects / Q000503:physiopathology; D015309:Glucose Clamp Technique; D006801:Humans; D006946:Hyperinsulinism / Q000139:chemically induced / Q000503:physiopathology*; D007328:Insulin / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D024821:Metabolic Syndrome / Q000502:physiology; D012039:Regional Blood Flow / Q000187:drug effects; D012965:Sodium Chloride / Q000008:administration & dosage; D018608:Ultrasonography, Doppler; D014654:Vascular Patency / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D000975:Antioxidants; D007328:Insulin; D014665:Vasodilator Agents; D012965:Sodium Chloride; D001205:Ascorbic Acid