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Research Article Free access | 10.1172/JCI1326

Bidirectional modulation of insulin action by amino acids.

M E Patti, E Brambilla, L Luzi, E J Landaker, and C R Kahn

Research Division, Joslin Diabetes Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.

Find articles by Patti, M. in: JCI | PubMed | Google Scholar

Research Division, Joslin Diabetes Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.

Find articles by Brambilla, E. in: JCI | PubMed | Google Scholar

Research Division, Joslin Diabetes Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.

Find articles by Luzi, L. in: JCI | PubMed | Google Scholar

Research Division, Joslin Diabetes Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.

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Research Division, Joslin Diabetes Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.

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Published April 1, 1998 - More info

Published in Volume 101, Issue 7 on April 1, 1998
J Clin Invest. 1998;101(7):1519–1529. https://doi.org/10.1172/JCI1326.
© 1998 The American Society for Clinical Investigation
Published April 1, 1998 - Version history
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Abstract

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.

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