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Unlike insulin, amino acids stimulate p70^S6K but not GSK-3 or glycogen synthase in human skeletal muscle

Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia Health System, Charlottesville, Virginia 22908

Submitted 4 April 2003 ; accepted in final form 25 November 2003

Insulin stimulates muscle glucose disposal via both glycolysis and glycogen synthesis. Insulin activates glycogen synthase (GS) in skeletal muscle by phosphorylating 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 70-kDa protein S6 kinase (p70^S6K), has also been implicated in the regulation of GSK-3 and GS by insulin. Amino acids potently stimulate p70^S6K, and recent studies on cultured muscle cells suggest that amino acids also inactivate GSK-3 and/or activate GS via activating p70^S6K. 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, p70^S6K, and GSK-3 phosphorylation, and on 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^-1·min^-1 x 6 h, n = 9), a physiological dose of insulin (1 mU·kg^-1·min^-1 euglycemic hyperinsulinemic clamp x 2 h, n = 6), or a pharmacological dose of insulin (20 mU·kg^-1·min^-1 euglycemic hyperinsulinemic clamp x 2 h, n = 9). Whole body glucose disposal rates were assessed by calculating the steady-state glucose infusion rates, and vastus lateralis muscle was biopsied before and at the end of the infusion. Both amino acid infusion and physiological hyperinsulinemia enhanced p70^S6K phosphorylation without affecting GSK-3 phosphorylation, but only physiological hyperinsulinemia also increased whole body glucose disposal and GS activity. In contrast, a pharmacological dose of insulin significantly increased whole body glucose disposal, p70^S6K, GSK-3 phosphorylation, and GS activity. We conclude that amino acids at physiological concentrations mediate p70^S6K but, unlike insulin, do not regulate GSK-3 and GS phosphorylation/activity in human skeletal muscle.

hyperinsulinemia; hyperaminoacidemia; signaling proteins; phosphorylation; in vivo

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