Abstract 5147: GLP-1 Improves Insulin-Stimulated Nitric Oxide-Dependent Vasodilator Responsiveness in Patients With Metabolic Syndrome

Abstract

Our previous work has shown that patients with metabolic syndrome (MetS) have impaired insulin-stimulated vasodilation, which may be involved in the development of hypertension and contribute to insulin resistance by affecting the glucose uptake. Glucagon-like peptide-1 (GLP-1), an amino acid gut hormone that stimulates both insulin secretion and sensitivity, is also provided of cardioprotective and vasoactive properties. We therefore examined the effects of exogenous GLP-1 on insulin-stimulated, nitric oxide (NO)-dependent vasodilation in patients with obesity-related MetS by use of the forearm perfusion technique. Forearm blood flow (FBF) responses to intra-arterial infusion of graded doses of acetylcholine (ACh; stimulus for endothelial release of NO) and sodium nitroprusside (SNP; exogenous NO donor) were assessed in 10 patients with MetS during coinfusion of either saline or regular insulin (0.2 mU/Kg/min). Thereafter, patients underwent to intra-arterial infusion of GLP-1 (30 ng/min for 45 minutes) and responses to ACh and SNP were then reassessed. In the absence of hyperinsulinemia, GLP-1 did not impact unstimulated FBF (from 3.5±0.2 [mean±SEM] to 3.6±0.3 ml/min/dl; P=0.59); similarly, exogenous GLP-1 did not affect vascular responses to both ACh (from 8.8±1.1 to 8.7±1.2 ml/min/dl at the highest dose; P=0.97) and SNP (from 10.7±0.6 to 9.6±0.7 ml/min/dl; P=0.68). In the presence of hyperinsulinemia, GLP-1 infusion was associated with mild increase in basal FBF (from 4.7±0.4 to 5.7±0.6 ml/min/dl; P=0.25); under those conditions, however, exogenous GLP-1 resulted in a significant improvement in vascular reactivity to both ACh (from 13.7±0.7 to 17.4±1.5 ml/min/dl; P=0.03) and SNP (from 12.7±1.0 to 15.9±1.2; P=0.02). In conclusion, exogenous GLP-1 improves both endothelium-dependent and -independent vasodilator responsiveness during hyperinsulinemia in patients with MetS. This suggests that GLP-1 may exert a facilitatory effect on insulin signaling to enhance NO-dependent reactivity in vascular smooth muscle. As a consequence, strategies targeting the GLP-1 system for treatment of type 2 diabetes might beneficially affect both metabolic and hemodynamic abnormalities associated with insulin resistance.