Amino acid and insulin signaling via the mTOR/p70 S6 kinase pathway. A negative feedback mechanism leading to insulin resistance in skeletal muscle cells

J Biol Chem. 2001 Oct 12;276(41):38052-60. doi: 10.1074/jbc.M106703200. Epub 2001 Aug 9.

Abstract

Amino acids have emerged as potent modulators of the mTOR/p70 S6 kinase pathway. The involvement of this pathway in the regulation of insulin-stimulated glucose transport was investigated in the present study. Acute exposure (1 h) to a balanced mixture of amino acids reduced insulin-stimulated glucose transport by as much as 55% in L6 muscle cells. The effect of amino acids was fully prevented by the specific mTOR inhibitor rapamycin. Time course analysis of insulin receptor substrate 1 (IRS-1)-associated phosphatidylinositol (PI) 3-kinase activity revealed that incubation with amino acids speeds up its time-dependent deactivation, leading to a dramatic suppression (-70%) of its activity after 30 min of insulin stimulation as compared with its maximal activation (5 min of stimulation). This accelerated deactivation of PI 3-kinase activity in amino acid-treated cells was associated with a concomitant and sustained increase in the phosphorylation of p70 S6 kinase. In marked contrast, inhibition of mTOR by rapamycin maintained PI 3-kinase maximally activated for up to 30 min. The marked inhibition of insulin-mediated PI 3-kinase activity by amino acids was linked to a rapamycin-sensitive increase in serine/threonine phosphorylation of IRS-1 and a decreased binding of the p85 subunit of PI 3-kinase to IRS-1. Furthermore, amino acids were required for the degradation of IRS-1 during long term insulin treatment. These results identify the mTOR/p70 S6 kinase signaling pathway as a novel modulator of insulin-stimulated glucose transport in skeletal muscle cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / metabolism*
  • Biological Transport
  • Cell Line
  • Enzyme Activation
  • Feedback
  • Glucose / metabolism
  • Hydrolysis
  • Insulin / metabolism*
  • Insulin Receptor Substrate Proteins
  • Insulin Resistance*
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Protein Kinases / metabolism*
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases / metabolism*
  • Signal Transduction*
  • TOR Serine-Threonine Kinases
  • Tyrosine / metabolism

Substances

  • Amino Acids
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • Tyrosine
  • Protein Kinases
  • Phosphatidylinositol 3-Kinases
  • TOR Serine-Threonine Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases
  • Glucose