Regulation of Glucose Uptake by Endothelin-1 in Human Skeletal Muscle in Vivo and in Vitro

Context: Expression of the vasoconstrictor and proinflammatory peptide endothelin (ET)-1 is increased in insulin-resistant (IR) subjects. Objective: The aim of this study was to investigate whether ET-1 regulates skeletal muscle glucose uptake in IR subjects in vivo and in cultured human skeletal muscle cells. Design and Participants: Eleven subjects participated in three protocols using brachial artery infusion of: A) BQ123 (10 nmol/min) and BQ788 (10 nmol/min) (ETA and ETB receptor antagonist, respectively), followed by coinfusion with insulin (0.05 mU/kg/min); B) insulin alone; and C) insulin followed by coinfusion with ET-1 (20 pmol/min). Main Outcome Measures: Forearm blood flow (FBF) and forearm glucose uptake (FGU) were determined. Glucose uptake and molecular signaling were determined in cultured skeletal muscle cells. Results: ETA/ETB receptor blockade increased FGU by 63% (P < 0.05). Coadministration of insulin caused a further 2-fold increase in FGU (P < 0.001). ETA/ETB receptor blockade combined with insulin resulted in greater FGU than insulin infusion alone (P < 0.005). ETA/ETB receptor blockade increased FBF by 30% (P < 0.05), with a further 16% increase (P < 0.01) during insulin coinfusion. ET-1 decreased basal FBF by 35% without affecting FGU. ET-1 impaired basal and insulin-stimulated glucose uptake in cultured muscle cells (P < 0.01) via an effect that was prevented by ETA/ETB receptor blockade. Conclusion: ETA/ETB receptor blockade enhances basal and insulin-stimulated glucose uptake in IR subjects. ET-1 directly impairs glucose uptake in skeletal muscle cells via a receptor-dependent mechanism. These data suggest that ET-1 regulates glucose metabolism via receptor-dependent mechanisms in IR subjects. (J Clin Endocrinol Metab 95: 2359-2366, 2010)