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Endothelin Limits Insulin Action in Obese/Insulin-Resistant Humans

¹ Division of Endocrinology and Metabolism, Indiana University School of Medicine, Indianapolis, Indiana
² Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
³ Amylin Pharmaceuticals, San Diego, California

Address correspondence and reprint requests to Kieren Mather, MD, FRCPC, Division of Endocrinology and Metabolism, Department of Medicine, Indiana University School of Medicine, CL459, 541 North Clinical Dr., Indianapolis, IN 46202. E-mail: kmather{at}iupui.edu

Abbreviations: AV, arteriovenous; ET-1, endothelin 1; IRS, insulin receptor substrate; LBF, leg blood flow; L-NMMA, N^G-monomethyl-L-arginine; LVC, leg vascular conductance; MAP, mean arterial pressure; NOx, total serum nitrate; PIP₂, phosphatidylinositol 4,5-bisphosphate; PKC, protein kinase C

The normal action of insulin to vasodilate and redistribute blood flow in support of skeletal muscle metabolism is impaired in insulin-resistant states. Increased endogenous endothelin contributes to endothelial dysfunction in obesity and diabetes. Here, we test the hypothesis that increased endogenous endothelin action also contributes to skeletal muscle insulin resistance via impairments in insulin-stimulated vasodilation. We studied nine lean and seven obese humans, measuring the metabolic and hemodynamic effects of insulin (300 mU · m^–2 · min^–1) alone and during femoral artery infusion of BQ123 (an antagonist of type A endothelin receptors, 1 µmol/min). Endothelin antagonism augmented skeletal muscle responses to insulin in obese subjects through changes in both leg blood flow (LBF) and glucose extraction. Insulin-stimulated LBF was significantly increased in obese subjects only. These changes, combined with differential effects on glucose extraction, resulted in augmented insulin-stimulated leg glucose uptake in obese subjects (54.7 ± 5.7 vs. 107.4 ± 18.9 mg/min with BQ123), with no change in lean subjects (103.7 ± 11.4 vs. 88.9 ± 16.3, P = 0.04 comparing BQ123 across groups). BQ123 allowed augmented leg glucose extraction in obese subjects even in the face of NOS antagonism. These findings suggest that increased endogenous endothelin action contributes to insulin resistance in skeletal muscle of obese humans, likely through both vascular and tissue effects.

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