Jamieson Emma, Chong Mark M W, Steinberg Gregory R, Jovanovska Valentina, Fam Barbara C, Bullen Denise V R, Chen Ye, Kemp Bruce E, Proietto Joseph, Kay Thomas W H, Andrikopoulos Sofianos
St. Vincent's Institute of Medical Research, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia.
J Biol Chem. 2005 Sep 9;280(36):31516-21. doi: 10.1074/jbc.M502163200. Epub 2005 Jun 27.
Suppressor of cytokine signaling 1 (SOCS1) is an intracellular inhibitor of cytokine, growth factor, and hormone signaling. Socs1-/- mice die before weaning from a multiorgan inflammatory disease. Neonatal Socs1-/- mice display severe hypoglycemia and hypoinsulinemia. Concurrent interferon gamma gene deletion (Ifng-/-) prevented inflammation and corrected the hypoglycemia. In hyperinsulinemic clamp studies, however, Socs1-/- Ifng-/- mice had enhanced hepatic insulin sensitivity demonstrated by greater suppression of endogenous glucose production compared with controls with no difference in glucose disposal. Socs1-/- Ifng-/- mice had elevated liver insulin receptor substrate 2 expression (IRS-2) and IRS-2 tyrosine phosphorylation. This was associated with lower phosphoenolpyruvate carboxykinase mRNA expression. These effects were not associated with elevated hepatic AMP-activated protein kinase activity. Hepatic insulin sensitivity and IRS-2 levels play central roles in the pathogenesis of type 2 diabetes. Socs1 deficiency increases IRS-2 expression and enhances hepatic insulin sensitivity in vivo indicating that inhibition of SOCS1 may be a logical strategy in type 2 diabetes.
细胞因子信号转导抑制因子1（SOCS1）是细胞因子、生长因子和激素信号转导的细胞内抑制剂。Socs1基因敲除小鼠在断奶前死于多器官炎症性疾病。新生Socs1基因敲除小鼠表现出严重的低血糖和低胰岛素血症。同时敲除干扰素γ基因（Ifng基因敲除）可预防炎症并纠正低血糖。然而，在高胰岛素钳夹研究中，与葡萄糖处置无差异的对照组相比，Socs1基因敲除Ifng基因敲除小鼠通过更大程度地抑制内源性葡萄糖生成表现出增强的肝脏胰岛素敏感性。Socs1基因敲除Ifng基因敲除小鼠的肝脏胰岛素受体底物2表达（IRS-2）和IRS-2酪氨酸磷酸化升高。这与磷酸烯醇式丙酮酸羧激酶mRNA表达降低有关。这些效应与肝脏AMP活化蛋白激酶活性升高无关。肝脏胰岛素敏感性和IRS-2水平在2型糖尿病发病机制中起核心作用。Socs1缺乏会增加IRS-2表达并增强体内肝脏胰岛素敏感性，表明抑制SOCS1可能是2型糖尿病的合理策略。
