Bidirectional modulation of insulin action by amino acids
Bidirectional modulation of insulin action by amino acids
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DOI：
10.1172/jci1326
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发表时间：
1998-04-01
影响因子：
15.9
通讯作者：
Kahn, CR
中科院分区：
文献类型：
--
作者：
Patti, ME;Brambilla, E;Kahn, CR
氨基酸已被证明可以刺激蛋白质合成，抑制蛋白质水解，并减少全身和前臂葡萄糖的处置，使用培养的肝癌细胞和肌管细胞，我们证明了氨基酸作为胰岛素靶组织中的新型信号元件。将细胞暴露于高生理浓度的氨基酸激活在蛋白质合成起始中重要的中间体，包括p70 S6激酶和PHAS-I，与胰岛素协同作用。这种刺激作用主要是由于支链氨基酸，特别是亮氨酸，并且可以通过其转氨产物酮异己酸再现。同时，氨基酸抑制胰岛素作用的早期步骤，所述胰岛素作用对葡萄糖转运和胰岛素生成的抑制至关重要，包括胰岛素刺激的IRS-1和IRS-2的酪氨酸磷酸化降低，降低grb 2和磷脂酰肌醇3-激酶p85亚基与IRS-1和IRS-2的结合，并显著抑制胰岛素刺激的磷脂酰肌醇3-激酶。总之，这些数据支持氨基酸作为维持蛋白质储存的特异性阳性信号，同时在多个水平上抑制胰岛素的其他作用的假设。这种胰岛素作用的双向调节表明激素和营养信号之间的串扰，并证明了营养因素导致胰岛素抵抗的新机制。
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.