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Physiological Hyperinsulinemia Stimulates p70^S6k Phosphorylation in Human Skeletal Muscle¹

Department of Internal Medicine, Division of Endocrinology, University of Virginia School of Medicine, Charlottesville, Virginia 22908

Address all correspondence and requests for reprints to: Eugene J. Barrett, M.D., Ph.D., Department of Internal Medicine, MR4-5116, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908. E-mail: ejb8x{at}virginia.edu

Abstract

Using tracer methods, insulin stimulates muscle protein synthesis in vitro, an effect not seen in vivo with physiological insulin concentrations in adult animals or humans. To examine the action of physiological hyperinsulinemia on protein synthesis using a tracer-independent method in vivo and identify possible explanations for this discrepancy, we measured the phosphorylation of ribosomal protein S6 kinase (P70^S6k) and eIF4E-binding protein (eIF4E-BP1), two key proteins that regulate messenger ribonucleic acid translation and protein synthesis. Postabsorptive healthy adults received either a 2-h insulin infusion (1 mU/min·kg; euglycemic insulin clamp; n = 6) or a 2-h saline infusion (n = 5). Vastus lateralis muscle was biopsied at baseline and at the end of the infusion period. Phosphorylation of P70^S6k and eIF4E-BP1 was quantified on Western blots after SDS-PAGE. Physiological increments in plasma insulin (42 ± 13 to 366 ± 36 pmol/L; P = 0.0002) significantly increased p70^S6k (P < 0.01), but did not affect eIF4E-BP1 phosphorylation in muscle. Plasma insulin declined slightly during saline infusion (P = 0.04), and there was no change in the phosphorylation of either p70^S6k or eIF4E-BP1. These findings indicate an important role of physiological hyperinsulinemia in the regulation of p70^S6k in human muscle. This finding is consistent with a potential role for insulin in regulating the synthesis of that subset of proteins involved in ribosomal function. The failure to enhance the phosphorylation of eIF4E-BP1 may in part explain the lack of a stimulatory effect of physiological hyperinsulinemia on bulk protein synthesis in skeletal muscle in vivo.

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