Amylin-mediated inhibition of insulin-stimulated glucose transport in skeletal muscle.
We examined the effects of amylin on 3-O-methyl-D-glucose (3-O-MG) transport in perfused rat hindlimb muscle under hyperinsulinemic (350 microU/ml, 2,100 pmol/l) conditions. Amylin at 100 nmol/l concentration inhibited 3-O-MG transport relative to control in all three basic muscle fiber types. Transport decreased in slow-twitch oxidative (from 5.65 +/- 1.13 to 3.46 +/- 0.71 micromol . g-1 . h-1), fast-twitch oxidative (from 6.84 +/- 0.90 to 4.84 +/- 0.76 micromol . g-1 . h-1), and fast-twitch glycolytic (from 1.27 +/- 0.20 to 0.60 +/- 0.05 micromol . g-1 . h-1) muscle. Amylin inhibition of insulin-stimulated glucose transport in skeletal muscle was accompanied by a 433 +/- 72% increase in intracellular glucose 6-phosphate (G-6-P) despite the absence of extracellular glucose. The source of hexose units for the formation and maintenance of G-6-P was likely glycogen. Amylin increased glycogenolysis, increased lactate formation, and decreased glycogen synthase activity. Furthermore, the kinetics of glycogen synthase suggest that this enzyme may control intracellular G-6-P concentration. Despite the large increase in G-6-P, no detectable increase in uridine diphosphate-N-acetylhexosamines occurred, suggesting that the proposed glucosamine pathway may not be involved in transport inhibition. However, decreases in uridine diphosphate hexoses were detected. Therefore, uridine or hexosamine-based metabolites may be involved in amylin action.
Castle
A L
AL
Exercise Physiology and Metabolism Laboratory, Department of Kinesiology and Health Education, University of Texas at Austin, Austin, Texas 78712, USA.
Kuo
C H
CH
Han
D H
DH
Ivy
J L
JL
D019325:3-O-Methylglucose / Q000493:pharmacokinetics*; D000682:Amyloid / Q000494:pharmacology* / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D019298:Glucose-6-Phosphate / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006006:Glycogen Synthase / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology; D006614:Hindlimb; D007328:Insulin / Q000494:pharmacology* / Q000502:physiology; D007329:Insulin Antagonists / Q000494:pharmacology; D058228:Islet Amyloid Polypeptide; D007773:Lactates / Q000378:metabolism; D018656:Muscle Fibers, Fast-Twitch / Q000187:drug effects / Q000378:metabolism*; D018657:Muscle Fibers, Slow-Twitch / Q000187:drug effects / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D010101:Oxygen Consumption; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley
D000682:Amyloid; D007328:Insulin; D007329:Insulin Antagonists; D058228:Islet Amyloid Polypeptide; D007773:Lactates; D019325:3-O-Methylglucose; D019298:Glucose-6-Phosphate; D006003:Glycogen; D006006:Glycogen Synthase