Amino acid and insulin signaling via the mTOR/p70 S6 kinase pathway. A negative feedback mechanism leading to insulin resistance in skeletal muscle cells.
Amino acid and insulin signaling via the mTOR/p70 S6 kinase pathway. A negative feedback mechanism leading to insulin resistance in skeletal muscle cells.
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DOI：
10.1074/jbc.m106703200
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发表时间：
2001-10
期刊：
影响因子：
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通讯作者：
Frédéric Tremblay;A. Marette
中科院分区：
文献类型：
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作者：
Frédéric Tremblay;A. Marette
氨基酸已成为 mTOR/p70 S6 激酶途径的有效调节剂。本研究调查了该途径在胰岛素刺激的葡萄糖转运调节中的作用。急性暴露（1 小时）于平衡的氨基酸混合物中，L6 肌细胞中胰岛素刺激的葡萄糖转运减少了 55%。特异性 mTOR 抑制剂雷帕霉素完全阻止了氨基酸的作用。对胰岛素受体底物 1 (IRS-1) 相关磷脂酰肌醇 (PI) 3 激酶活性的时程分析表明，与氨基酸一起孵育会加速其时间依赖性失活，导致与最大激活（刺激 5 分钟）相比，胰岛素刺激 30 分钟后其活性显着抑制（-70%）。氨基酸处理的细胞中 PI 3 激酶活性的加速失活与 p70 S6 激酶磷酸化的伴随且持续的增加有关。与此形成鲜明对比的是，雷帕霉素对 mTOR 的抑制使 PI 3-激酶保持最大程度的激活长达 30 分钟。氨基酸对胰岛素介导的 PI 3 激酶活性的显着抑制与雷帕霉素敏感的 IRS-1 丝氨酸/苏氨酸磷酸化增加以及 PI 3 激酶 p85 亚基与 IRS-1 结合的减少有关。此外，在长期胰岛素治疗过程中，IRS-1 的降解需要氨基酸。这些结果表明 mTOR/p70 S6 激酶信号通路是骨骼肌细胞中胰岛素刺激的葡萄糖转运的新型调节剂。
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.