Mechanism of Amino Acid-Induced Skeletal Muscle Insulin Resistance in Humans Michael Krebs 1 , Martin Krssak 1 , Elisabeth Bernroider 1 , Christian Anderwald 1 , Attila Brehm 1 , Martin Meyerspeer 1 2 , Peter Nowotny 1 , Erich Roth 3 , Werner Waldhäusl 1 and Michael Roden 1 1 Division of Endocrinology and Metabolism, Department of Internal Medicine III, University of Vienna Medical School, Vienna, Austria 2 NMR-Group, Institute of Medical Physics, University of Vienna Medical School, Vienna, Austria 3 Department of Surgery, University of Vienna Medical School, Vienna, Austria Abstract Plasma concentrations of amino acids are frequently elevated in insulin-resistant states, and a protein-enriched diet can impair glucose metabolism. This study examined effects of short-term plasma amino acid (AA) elevation on whole-body glucose disposal and cellular insulin action in skeletal muscle. Seven healthy men were studied for 5.5 h during euglycemic (5.5 mmol/l), hyperinsulinemic (430 pmol/l), fasting glucagon (65 ng/l), and growth hormone (0.4 μg/l) somatostatin clamp tests in the presence of low (∼1.6 mmol/l) and increased (∼4.6 mmol/l) plasma AA concentrations. Glucose turnover was measured with d -6,6- 2 H 2 glucose. Intramuscular concentrations of glycogen and glucose-6-phosphate (G6P) were monitored using 13 C and 31 P nuclear magnetic resonance spectroscopy, respectively. A ∼2.1-fold elevation of plasma AAs reduced whole-body glucose disposal by 25% ( P < 0.01). Rates of muscle glycogen synthesis decreased by 64% (180–315 min, 24 ± 3; control, 67 ± 10 μmol · l −1 · min −1 ; P < 0.01), which was accompanied by a reduction in G6P starting at 130 min (ΔG6P 260–300 min , 18 ± 19; control, 103 ± 33 μmol/l; P < 0.05). In conclusion, plasma amino acid elevation induces skeletal muscle insulin resistance in humans by inhibition of glucose transport/phosphorylation, resulting in marked reduction of glycogen synthesis. Footnotes Address correspondence and reprint requests to Michael Roden, MD, Division of Endocrinology and Metabolism, Department of Internal Medicine III, University of Vienna Medical School, Währinger Gürtel 18-20, A-1090 Vienna, Austria. E-mail: michael.roden{at}akh-wien.ac.at . Received for publication 18 September 2001 and accepted in revised form 26 November 2001. AA, amino acid; APE, atom percent excess; EGP, endogenous glucose production; FFA, free fatty acid; G6P, glucose-6-phosphate; GIR, glucose infusion rate; HPLC, high-performance liquid chromatography; NMR, nuclear magnetic resonance; PCr, phosphocreatine; Pi, inorganic phosphate; R a , rate of glucose appearance; R d , rate of glucose disappearance; RIA, radioimmunoassay. DIABETES