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) (ET(A) and ET(B) 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

ET(A)/ET(B) receptor blockade increased FGU by 63% (P < 0.05). Coadministration of insulin caused a further 2-fold increase in FGU (P < 0.001). ET(A)/ET(B) receptor blockade combined with insulin resulted in greater FGU than insulin infusion alone (P < 0.005). ET(A)/ET(B) 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 ET(A)/ET(B) receptor blockade.

CONCLUSION

ET(A)/ET(B) 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.