Dynamic functional relay between insulin receptor substrate 1 and 2 in hepatic insulin signaling during fasting and feeding
Dynamic functional relay between insulin receptor substrate 1 and 2 in hepatic insulin signaling during fasting and feeding
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DOI：
10.1016/j.cmet.2008.05.007
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发表时间：
2008-07-01
期刊：
影响因子：
29
通讯作者：
Kadowaki, Takashi
中科院分区：
文献类型：
--
作者：
Kubota, Naoto;Kubota, Tetsuya;Kadowaki, Takashi
胰岛素受体底物 (Irs) 介导胰岛素的代谢作用。在这里，我们表明肝脏 Irs1 和 Irs2 在调节葡萄糖稳态中以不同的方式发挥作用。与Irs2相关的PI3K活性在禁食期间开始增加，在重新进食后立即达到峰值，然后迅速下降。相比之下，与 Irs1 相关的 PI3K 活性在重新喂食后几小时开始增加，并在此后达到峰值。数据表明，Irs2 主要在禁食期间和重新喂食后立即发挥作用，而 Irs1 主要在重新喂食后发挥作用。事实上，肝脏特异性 Irs1 敲除小鼠在禁食期间未能表现出胰岛素抵抗，但在重新喂食后表现出胰岛素抵抗；相反，肝脏特异性 Irs2 敲除小鼠在禁食期间表现出胰岛素抵抗，但在重新进食后则没有表现出胰岛素抵抗。我们提出了禁食和进食期间肝胰岛素信号传导中 Irs1 和 Irs2 之间存在动态中继的概念。
Insulin receptor substrate (Irs) mediates metabolic actions of insulin. Here, we show that hepatic Irs1 and Irs2function in a distinct manner in the regulation of glucose homeostasis. The PI3K activity associated with Irs2 began to increase during fasting, reached its peak immediately after refeeding, and decreased rapidly thereafter. By contrast, the PI3K activity associated with Irs1 began to increase a few hours after refeeding and reached its peak thereafter. The data indicate that Irs2 mainly functions during fasting and immediately after refeeding, and Irs1 functions primarily after refeeding. In fact, liver-specific Irs1-knockout mice failed to exhibit insulin resistance during fasting, but showed insulin resistance after refeeding; conversely, liver-specific Irs2-knockout mice displayed insulin resistance during fasting but not after refeeding. We propose the concept of the existence of a dynamic relay between Irs1 and Irs2 in hepatic insulin signaling during fasting and feeding.