title: Physiological hyperinsulinemia impairs insulin-stimulated glycogen synthase activity and glycogen synthesis.
abstract: Although chronic hyperinsulinemia has been shown to induce insulin resistance, the basic cellular mechanisms responsible for this phenomenon are unknown. The present study was performed 1) to determine the time-related effect of physiological hyperinsulinemia on glycogen synthase (GS) activity, hexokinase II (HKII) activity and mRNA content, and GLUT-4 protein in muscle from healthy subjects, and 2) to relate hyperinsulinemia-induced alterations in these parameters to changes in glucose metabolism in vivo. Twenty healthy subjects had a 240-min euglycemic insulin clamp study with muscle biopsies and then received a low-dose insulin infusion for 24 (n = 6) or 72 h (n = 14) (plasma insulin concentration = 121 +/- 9 or 143 +/- 25 pmol/l, respectively). During the baseline insulin clamp, GS fractional velocity (0.075 +/- 0.008 to 0.229 +/- 0.02, P < 0.01), HKII mRNA content (0.179 +/- 0.034 to 0.354 +/- 0.087, P < 0.05), and HKII activity (2.41 +/- 0.63 to 3.35 +/- 0.54 pmol x min(-1) x ng(-1), P < 0.05), as well as whole body glucose disposal and nonoxidative glucose disposal, increased. During the insulin clamp performed after 24 and 72 h of sustained physiological hyperinsulinemia, the ability of insulin to increase muscle GS fractional velocity, total body glucose disposal, and nonoxidative glucose disposal was impaired (all P < 0.01), whereas the effect of insulin on muscle HKII mRNA, HKII activity, GLUT-4 protein content, and whole body rates of glucose oxidation and glycolysis remained unchanged. Muscle glycogen concentration did not change [116 +/- 28 vs. 126 +/- 29 micromol/kg muscle, P = nonsignificant (NS)] and was not correlated with the change in nonoxidative glucose disposal (r = 0.074, P = NS). In summary, modest chronic hyperinsulinemia may contribute directly (independent of change in muscle glycogen concentration) to the development of insulin resistance by its impact on the GS pathway.
authors: Division of Diabetes, Department of Medicine, The University of Texas Health Science Center, San Antonio, Texas 78284, USA.
authors: P
authors: P
authors: Iozzo
authors: T
authors: T
authors: Pratipanawatr
authors: H
authors: H
authors: Pijl
authors: C
authors: C
authors: Vogt
authors: V
authors: V
authors: Kumar
authors: R
authors: R
authors: Pipek
authors: M
authors: M
authors: Matsuda
authors: L J
authors: LJ
authors: Mandarino
authors: K J
authors: KJ
authors: Cusi
authors: R A
authors: RA
authors: DeFronzo
mesh_terms: D000328:Adult; D005260:Female; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4; D006003:Glycogen / Q000096:biosynthesis*; D006006:Glycogen Synthase / Q000378:metabolism*; D006593:Hexokinase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006946:Hyperinsulinism / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D012016:Reference Values; D013997:Time Factors
chemical_list: D051275:Glucose Transporter Type 4; D007328:Insulin; D007527:Isoenzymes; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; C495692:SLC2A4 protein, human; D006003:Glycogen; D006006:Glycogen Synthase; D006593:Hexokinase; D005947:Glucose