The physiological and pathophysiological role of IRS-1 and IRS-2 in the liver

在2型糖尿病的肝脏中，PEPCK通路对胰岛素的作用有抵抗性，通过糖异生的上调导致高血糖。另一方面，胰岛素通路过度活跃，上调SREBP1c，导致脂肪变性和高甘油三酯血症。为什么胰岛素在糖代谢“高血糖症”中的作用受损和胰岛素在脂质代谢“脂肪变性”中的作用夸大在2型糖尿病患者的肝脏中同时存在？为了研究这些机制，我们给我们的LIRS1KO和LIRS2KO小鼠喂食HF饮食。在对照组小鼠中，HF饮食中IRS1的表达水平没有任何变化。相反，与IRS1不同的是，在HF饮食的对照组小鼠中，IRS2发生了严重的下调。HF饮食的LIRS1KO小鼠表现出严重的葡萄糖耐受不良和肝脏脂肪变性抑制。相比之下，LIRS2KO小鼠仅表现出轻度葡萄糖耐受不良和肝脏脂肪变性。在HF饮食下，IRS2被深度下调，这与葡萄糖代谢失调有因果关系。另一方面，高胰岛素介导的IRS1信号增加，因为IRS1没有下调。因此，它与脂肪变性有因果关系。

In the liver in type 2 diabetes, PEPCK pathway is resistant to insulin action, leading to hyperglycemia via upregulation of gluconeogenesis. On the other hand, insulin pathway is superactive to upregulate SREBP1c to cause steatosis and hypertriglyceridemia. Why impaired insulin action in glucose metabolism "hyperglycemia"and exaggerated insulin action in lipid metabolism"steatosis, coexist in the liver in type 2 diabetes? To investigate these mechanisms, we fed our LIRS1KO and LIRS2KO mice on a HF diet. IRS1 expression levels on a HF diet did not show any change in the control mice. In contrast, unlike IRS1, IRS2 underwent profound downregulation in the control mice on a HF diet. LIRS1KO mice on a HF diet showed severe glucose intolerance and suppression of hepatic steatosis. In contrast, LIRS2KO mice showed only mild glucose intolerance and hepatic steatosis. Under a HF diet, IRS2 is profoundly downregulated, which is causally involved in the dysregulation of glucose metabolism. On the other hand, hyperinsulinemia-mediated IRS1 signal is rather increased, because IRS1 is not downregulated. So, it is causally involved in the steatosis.