Mechanism of amino acid-induced skeletal muscle insulin resistance in humans.
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 microg/l) somatostatin clamp tests in the presence of low (approximately 1.6 mmol/l) and increased (approximately 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 approximately 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 plus minus 3; control, 67 plus minus 10 micromol center dot l(-1) center dot min(-1); P < 0.01), which was accompanied by a reduction in G6P starting at 130 min (DeltaG6P(260--300 min), 18 plus minus 19; control, 103 plus minus 33 micromol/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.
Krebs
Michael
M
Division of Endocrinology and Metabolism, Department of Internal Medicine III, University of Vienna Medical School, Vienna, Austria.
Krssak
Martin
M
Bernroider
Elisabeth
E
Anderwald
Christian
C
Brehm
Attila
A
Meyerspeer
Martin
M
Nowotny
Peter
P
Roth
Erich
E
Waldhäusl
Werner
W
Roden
Michael
M
D000244:Adenosine Diphosphate / Q000032:analysis; D000328:Adult; D000596:Amino Acids / Q000097:blood / Q000494:pharmacology*; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism; D003903:Deuterium; D004837:Epinephrine / Q000097:blood; D005215:Fasting; D005934:Glucagon / Q000097:blood; D015309:Glucose Clamp Technique; D019298:Glucose-6-Phosphate / Q000032:analysis; D006003:Glycogen / Q000032:analysis / Q000096:biosynthesis; D019382:Human Growth Hormone / Q000097:blood; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D006863:Hydrogen-Ion Concentration; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D007333:Insulin Resistance; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D018482:Muscle, Skeletal / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D010710:Phosphates / Q000032:analysis; D010725:Phosphocreatine / Q000032:analysis; D010766:Phosphorylation; D013004:Somatostatin / Q000097:blood
D000596:Amino Acids; D001786:Blood Glucose; D007328:Insulin; D010710:Phosphates; D010725:Phosphocreatine; D019382:Human Growth Hormone; D013004:Somatostatin; D019298:Glucose-6-Phosphate; D000244:Adenosine Diphosphate; D006003:Glycogen; D005934:Glucagon; D003903:Deuterium; D006854:Hydrocortisone; D004837:Epinephrine