Inhibition of PTP1B restores IRS1-mediated hepatic insulin signaling in IRS2-deficient mice.
Inhibition of PTP1B restores IRS1-mediated hepatic insulin signaling in IRS2-deficient mice.
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DOI：
10.2337/db09-0796
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发表时间：
2010-03
期刊：
影响因子：
7.7
通讯作者：
Valverde AM
中科院分区：
文献类型：
--
作者：
González-Rodríguez A;Mas Gutierrez JA;Sanz-González S;Ros M;Burks DJ;Valverde AM
胰岛素受体底物2（IRS 2）完全缺失的小鼠会出现高血糖症、肝脏胰岛素信号传导受损和新生血管生成增加，而蛋白酪氨酸磷酸酶（PTP）1B缺陷的小鼠则表现出相反的肝脏表型，其特征在于对胰岛素的敏感性增加。为了确定这两种信号通路在肝脏代谢调节中的关系，我们使用遗传和药理学方法研究了抑制PTP 1B对IRS 2 −/−小鼠肝脏胰岛素信号传导和促胰岛素生成酶表达的影响。我们分析了IRS 2 −/−和IRS 2 −/−/PTP 1B −/−小鼠肝脏和分离肝细胞中的葡萄糖稳态和胰岛素信号传导。此外，在对照组和用白藜芦醇（红葡萄酒中的一种抗氧化剂）处理的IRS 2 −/−小鼠中评估了肝脏胰岛素信号传导。在高血糖IRS 2 −/−小鼠的肝脏中，PTP 1B的表达水平及其与胰岛素受体（IR）的相关性增加。在双突变小鼠中PTP 1B的缺失恢复了肝脏IRS 1介导的磷脂酰肌醇（PI）3-激酶/Akt/Foxo 1信号传导。此外，白藜芦醇治疗高血糖IRS 2 −/−小鼠降低肝脏PTP 1B mRNA并抑制PTP 1B活性，从而恢复IRS 1介导的PI 3-激酶/Akt/Foxo 1信号传导和外周胰岛素敏感性。通过调节IR的磷酸化状态，PTB 1B决定了肝脏对胰岛素的敏感性，并在肝脏胰岛素作用的调节中IRS 1和IRS 2之间的相互作用中发挥独特的作用。
Mice with complete deletion of insulin receptor substrate 2 (IRS2) develop hyperglycemia, impaired hepatic insulin signaling, and elevated gluconeogenesis, whereas mice deficient for protein tyrosine phosphatase (PTP)1B display an opposing hepatic phenotype characterized by increased sensitivity to insulin. To define the relationship between these two signaling pathways in the regulation of liver metabolism, we used genetic and pharmacological approaches to study the effects of inhibiting PTP1B on hepatic insulin signaling and expression of gluconeogenic enzymes in IRS2−/− mice. We analyzed glucose homeostasis and insulin signaling in liver and isolated hepatocytes from IRS2−/− and IRS2−/−/PTP1B−/− mice. Additionally, hepatic insulin signaling was assessed in control and IRS2−/− mice treated with resveratrol, an antioxidant present in red wine. In livers of hyperglycemic IRS2−/− mice, the expression levels of PTP1B and its association with the insulin receptor (IR) were increased. The absence of PTP1B in the double-mutant mice restored hepatic IRS1-mediated phosphatidylinositol (PI) 3-kinase/Akt/Foxo1 signaling. Moreover, resveratrol treatment of hyperglycemic IRS2−/− mice decreased hepatic PTP1B mRNA and inhibited PTP1B activity, thereby restoring IRS1-mediated PI 3-kinase/Akt/Foxo1 signaling and peripheral insulin sensitivity. By regulating the phosphorylation state of IR, PTB1B determines sensitivity to insulin in liver and exerts a unique role in the interplay between IRS1 and IRS2 in the modulation of hepatic insulin action.