Physiological hyperinsulinemia impairs insulin-stimulated glycogen synthase activity and glycogen synthesis

Patricia Iozzo, Thonchai Pratipanawatr, Hanno Pijl, Christoph Vogt, Vineeta Kumar, Ruben Pipek, Masafumi Matsuda, Lawrence J. Mandarino, Kenneth J. Cusi, Ralph A. DeFronzo

Research output: Contribution to journalArticlepeer-review

44 Scopus citations


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·min-1·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 μmol/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.

Original languageEnglish (US)
Pages (from-to)E712-E719
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Issue number5 43-5
StatePublished - May 2001
Externally publishedYes


  • Glucose transporter 4
  • Hexokinase II
  • Insulin resistance
  • Skeletal muscle

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)


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