Bidirectional Modulation of Insulin Action by Amino Acids

Amino acids have been shown to stimulate protein synthe-sis, inhibit proteolysis, and decrease whole-body and fore-arm glucose disposal. Using cultured hepatoma and myo-tube 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 synthe-sis, 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 repro-duced by its transamination product, ketoisocaproic acid. Concurrently, amino acids inhibit early steps in insulin ac-tion critical for glucose transport and inhibition of gluco-neogenesis, 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.