Bidirectional modulation of insulin action by amino acids

J Clin Invest. 1998 Apr 1;101(7):1519-29. doi: 10.1172/JCI1326.


Amino acids have been shown to stimulate protein synthesis, inhibit proteolysis, and decrease whole-body and forearm glucose disposal. Using cultured hepatoma and myotube cells, we demonstrate that amino acids act as novel signaling elements in insulin target tissues. Exposure of cells to high physiologic concentrations of amino acids activates intermediates important in the initiation of protein synthesis, including p70 S6 kinase and PHAS-I, in synergy with insulin. This stimulatory effect is largely due to branched chain amino acids, particularly leucine, and can be reproduced by its transamination product, ketoisocaproic acid. Concurrently, amino acids inhibit early steps in insulin action critical for glucose transport and inhibition of gluconeogenesis, including decreased insulin-stimulated tyrosine phosphorylation of IRS-1 and IRS-2, decreased binding of grb 2 and the p85 subunit of phosphatidylinositol 3-kinase to IRS-1 and IRS-2, and a marked inhibition of insulin-stimulated phosphatidylinositol 3-kinase. Taken together, these data support the hypothesis that amino acids act as specific positive signals for maintenance of protein stores, while inhibiting other actions of insulin at multiple levels. This bidirectional modulation of insulin action indicates crosstalk between hormonal and nutritional signals and demonstrates a novel mechanism by which nutritional factors contribute to insulin resistance.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Amino Acids / pharmacology*
  • Androstadienes / pharmacology
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Carrier Proteins*
  • Cell Cycle Proteins
  • Cell Division / drug effects
  • Cells, Cultured
  • Enzyme Activation
  • Flavonoids / pharmacology
  • GRB2 Adaptor Protein
  • Humans
  • Insulin / pharmacology*
  • Insulin Receptor Substrate Proteins
  • Liver / metabolism*
  • Phosphatidylinositol 3-Kinases / physiology
  • Phosphoproteins / metabolism
  • Polyenes / pharmacology
  • Protein-Serine-Threonine Kinases*
  • Proteins / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases / metabolism*
  • Signal Transduction / drug effects
  • Sirolimus
  • Wortmannin


  • Adaptor Proteins, Signal Transducing
  • Amino Acids
  • Androstadienes
  • Carrier Proteins
  • Cell Cycle Proteins
  • EIF4EBP1 protein, human
  • Flavonoids
  • GRB2 Adaptor Protein
  • GRB2 protein, human
  • IRS1 protein, human
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Phosphoproteins
  • Polyenes
  • Proteins
  • Proto-Oncogene Proteins
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
  • Sirolimus
  • Wortmannin