Insulin Causes Endothelial Dysfunction in Humans

Abstract

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 (nϭ9), subjects underwent both a time-control saline study and a euglycemic low-dose insulin (insulin Ϸ110 pmol/L) clamp for 6 hours. Study B (nϭ5) was identical to study A except that the euglycemic clamp was performed at high physiological insulin concentrations (Ϸ440 pmol/L). In study C (nϭ7), subjects underwent two 4-hour euglycemic insulin (Ϸ110 pmol/L) clamps with and without the concomitant infusion of an antioxidant (vitamin C). In study D (nϭ4), 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 endotheliumindependent 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. (Circulation. 2002;105:576-582.)

Circulating endothelial cells are elevated in patients with type 2 diabetes mellitus independently of HbA1c

“…A recent report documenting a disturbed antioxidant defence mechanism associated with insulin resistance may support a hypothesis that insulin resistance rather than hyperglycaemia per se is primarily responsible for the increase in number of CECs in type 2 diabetics [30]. This is supported by a previous observation that endothelium-dependent vasodilatation is impaired in normal volunteers subjected to more than 4 h of euglycaemic hyperinsulinaemia, an effect that is reversed by vitamin C [34]. Future studies in patients with type 1 diabetes mellitus as well as correlation of the number CECs with insulin levels in a larger cohort of patients with type 2 diabetes mellitus would serve to further address this hypothesis.…”

Effects of glucose tolerance on the changes provoked by glucose ingestion in microvascular function

“…In humans, support for this notion derives mostly from studies using the OGTT as the stimulus, and flow-mediated dilatation of large arteries as the index of endothelial function [23][24][25]. Rather surprisingly, the results of these studies are not consistent [17,19] despite the fact that hyperinsulinaemia itself has been claimed to have a selective, major negative effect on this segment of the vascular tree [39,40]. The evidence in resistance vessels is scarce [22,41], comes from a single laboratory and describes an inhibitory effect that is small (ACh response reduced by 20%), only detectable for unphysiological degrees of hyperglycaemia (over 16 mmol/l) maintained for 6 h and effectively prevented by a very small gradient (35 pmol/l) of hyperinsulinaemia.…”

Insulin sensitivity in Chinese ovo-lactovegetarians compared with omnivores

“…Impaired insulin sensitivity is also associated with impaired vascular endothelial function that may help to account for increased cardiovascular risk (Arcaro et al, 2002). Measurement of insulin sensitivity is an important tool for elucidating the pathophysiology of these diseases.…”