Insulin impairs endothelium-dependent vasodilation independent of insulin sensitivity or lipid profile

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Abstract
Insulin resistance is a risk factor for atherosclerosis and is associated with hyperinsulinemia, abnormal lipid profile, and hypertension. Whether hyperinsulinemia affects vascular function independent of insulin resistance or other metabolic risk factors is unknown. This investigation aimed to assess the effects of hyperinsulinemia on endothelial function in subjects with a spectrum of insulin sensitivity and lipid profile. Endothelium-dependent (flow-mediated dilation, FMD) and -independent (nitroglycerin) responses of the brachial artery were studied by high-resolution ultrasound before and during hyperinsulinemia (euglycemic clamp) in 25 normoglycemic, normotensive subjects. Participants were divided into an insulin-sensitive and an insulin-resistant subgroup based on their sensitivity index values, with a cutoff of 8, and into a normal-cholesterol and a high-cholesterol subgroup based on their total cholesterol levels, with a cutoff of 5.2 mmol/l (200 mg/dl). In the whole population, FMD was lower during hyperinsulinemia compared with baseline (2.3 ± 0.6% vs. 6 ± 0.6%; P < 0.001). Resting FMD was lower in the insulin-resistant subgroup compared with the insulin-sensitive subgroup (4.2 ± 0.9% vs. 7.4 ± 0.8%; P = 0.014) and in the high-cholesterol subjects compared with the normal-cholesterol subjects (4.4 ± 0.7% vs. 8 ± 0.7%; P = 0.002). Hyperinsulinemia decreased FMD in both the insulin-sensitive (from 7.4 ± 0.8% to 3.6 ± 0.4%; P < 0.001) and insulin-resistant (from 4.2% to 1.22%; P = 0.012) subgroups and in both the normal-cholesterol (from 8 ± 0.7% to 3.9 ± 0.4%; P < 0.001) and high-cholesterol (from 4.4 ± 0.7% to 1.1 ± 0.8%; P = 0.01) participants. Acute hyperinsulinemia impairs conduit vessel endothelial function independent of insulin sensitivity and lipid profile. Insulin may trigger endothelial dysfunction and promote atherosclerosis.