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1 Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia Health System, Charlottesville, VA, USA
* To whom correspondence should be addressed. E-mail: zl3e{at}virginia.edu.
Insulin stimulates muscle glucose disposal via both glycolysis and glycogen synthesis. Insulin activates glycogen synthase (GS) in skeletal muscle by phosphorylating protein kinase B (PKB or Akt) which in turn phosphorylates and inactivates glycogen synthase kinase 3 (GSK-3), with subsequent activation of GS. A rapamycin-sensitive pathway, most likely acting via ribosomal protein S6 kinase (p70S6K), has also been implicated in the regulation of GSK-3 and GS by insulin. Amino acids potently stimulate p70S6K and recent studies on cultured muscle cells suggest that amino acids also inactivate GSK-3 and/or activate GS via activating p70S6K. To assess the physiological relevance of these findings to normal human physiology, we compared the effects of amino acids and insulin on whole body glucose disposal, p70S6K and GSK-3 phosphorylation, and the activity of GS in vivo in skeletal muscle of 24 healthy human volunteers. After an overnight fast, subjects received intravenously either a mixed amino acid solution (1.26 µmol/kg/min x 6 hours, n=9), physiologic dose insulin (1 mU/kg/min euglycemic hyperinsulinemic clamp x 2 hours, n=6) or pharmacologic dose insulin (20 mU/kg/min euglycemic hyperinsulinemic clamp x 2 hours, n=9). Whole body glucose disposal rates were assessed by calculating the steady-state glucose infusion rates and vastus lateralis muscle was biopsied prior to and at the end of the infusion. Both amino acid infusion and physiologic hyperinsulinemia enhanced p70S6K phosphorylation without affecting GSK-3 phosphorylation; but only physiologic hyperinsulinemia also increased whole body glucose disposal and GS activity. In contrast, pharmacologic dose insulin significantly increased whole body glucose disposal, p70S6K and GSK-3 phosphorylation and GS activity. We conclude that amino acids at physiologic concentrations mediate p70S6K but, unlike insulin, do not regulate GSK-3 and GS phosphorylation/activity in human skeletal muscle.
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