Overactivation of S6 Kinase 1 as a Cause of Human Insulin Resistance During Increased Amino Acid Availability

• Published in: Diabetes (New York, N.Y.) Vol. 54; no. 9; pp. 2674 - 2684
• Main Authors: TREMBLAY, Frédérie, KREBS, Michael, DOMBROWSKI, Luce, BREHM, Attila, BERNROIDER, Elisabeth, ROTH, Erich, NOWOTNY, Peter, WALDHHUSL, Werner, MARETTE, Andre, RODEN, Michael
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.09.2005
• Subjects: Adult; Amino acids; Amino Acids - administration & dosage; Amino Acids - blood; Amino Acids - metabolism; Biological and medical sciences; Biopsy; Cells, Cultured; Development and progression; Diabetes; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme Activation - physiology; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Glucose; Glucose - metabolism; Humans; Insulin resistance; Insulin Resistance - physiology; Kinases; Male; Medical sciences; Metabolism; Muscle, Skeletal - cytology; Musculoskeletal system; Observations; Phosphorylation; Plasma; Proteins; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Austria; Endocrinopathy; Human; Enzyme; Kinase; Transferases; Aminoacid; Diabetes mellitus; Insulin resistance
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.54.9.2674

Overactivation of S6 Kinase 1 as a Cause of Human Insulin Resistance During Increased Amino Acid Availability Frédéric Tremblay 1 , Michael Krebs 2 , Luce Dombrowski 1 , Attila Brehm 2 , Elisabeth Bernroider 2 , Erich Roth 3 , Peter Nowotny 2 , Werner Waldhäusl 2 , André Marette 1 and Michael Roden 2 4 1 Department of Physiology and Lipid Research Unit, Laval University Hospital Research Center, Ste-Foy, Québec, Canada 2 Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria 3 Department of Surgery, Medical University of Vienna,Vienna, Austria 4 1. Medical Department, Hanusch Hospital, Vienna, Austria Address correspondencereprint requests to Michael Roden, MD, Department of Internal Medicine III, Währinger Gürtel 18–20, A-1090 Vienna, Austria. E-mail: michael.roden{at}meduniwien.ac.at . Or André Marette, PhD, Lipid Research Unit, CHUL Research Center, Ste-Foy, Québec, G1V 4G2, Canada. E-mail: andre.marette{at}crchul.ulaval.ca Abstract To examine the molecular mechanisms by which plasma amino acid elevation impairs insulin action, we studied seven healthy men twice in random order during infusion of an amino acid mixture or saline (total plasma amino acid ∼6 vs. ∼2 mmol/l). Somatostatin-insulin-glucose clamps created conditions of low peripheral hyperinsulinemia (∼100 pmol/l, 0–180 min) and prandial-like peripheral hyperinsulinemia (∼430 pmol/l, 180–360 min). At low peripheral hyperinsulinemia, endogenous glucose production (EGP) did not change during amino acid infusion but decreased by ∼70% during saline infusion (EGP 150–180 min 11 ± 1 vs. 3 ± 1 μmol · kg −1 · min −1 , P = 0.001). Prandial-like peripheral hyperinsulinemia completely suppressed EGP during both protocols, whereas whole-body rate of glucose disappearance ( R d ) was ∼33% lower during amino acid infusion ( R d 330–360 min 50 ± 4 vs. 75 ± 6 μmol · kg −1 · min −1 , P = 0.002) indicating insulin resistance. In skeletal muscle biopsies taken before and after prandial-like peripheral hyperinsulinemia, plasma amino acid elevation markedly increased the ability of insulin to activate S6 kinase 1 compared with saline infusion (∼3.7- vs. ∼1.9-fold over baseline). Furthermore, amino acid infusion increased the inhibitory insulin receptor substrate-1 phosphorylation at Ser312 and Ser636/639 and decreased insulin-induced phosphoinositide 3-kinase activity. However, plasma amino acid elevation failed to reduce insulin-induced Akt/protein kinase B and glycogen synthase kinase 3α phosphorylation. In conclusion, amino acids impair 1 ) insulin-mediated suppression of glucose production and 2 ) insulin-stimulated glucose disposal in skeletal muscle. Our results suggest that overactivation of the mammalian target of rapamycin/S6 kinase 1 pathway and inhibitory serine phosphorylation of insulin receptor substrate-1 underlie the impairment of insulin action in amino acid–infused humans. 4E-BP1, eukaryotic initiation factor 4E–binding protein 1 EGP, endogenous glucose production FFA, free fatty acid GSK, glycogen synthase kinase IRS, insulin receptor substrate MEM, minimum essential medium mTOR, mammalian target of rapamycin PI, phosphoinositide PKB, protein kinase B S6K1, S6 kinase 1 Footnotes F.T. and M.K. contributed equally to this study. F.T. is currently affiliated with the Department of Biochemistry, McGill University, Montréal, Québec, Canada. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted May 27, 2005. Received December 13, 2004. DIABETES