Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice
Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice
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DOI：
10.2337/diabetes.52.11.2784
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发表时间：
2003-11-01
期刊：
影响因子：
7.7
通讯作者：
Mooney, RA
中科院分区：
文献类型：
--
作者：
Klover, PJ;Zimmers, TA;Mooney, RA
白介素6是与肥胖和2型糖尿病的胰岛素抵抗相关的几种促炎细胞因子之一。然而，在体内几乎没有直接证据表明IL-6在胰岛素抵抗中起到了致病作用。在这里，门静脉胰岛素攻击前连续5天皮下注射hIL-6会导致小鼠肝脏早期胰岛素受体信号的损害。重要的是，持续输注的IL-6水平提高了6倍，与肥胖患者的水平相似。与肝脏对IL-6的反应一致，IL-6处理的小鼠肝脏中STAT3的磷酸化在第5天增加。长期输注IL-6还使肝脏胰岛素受体自身磷酸化减少60%，胰岛素受体底物-1和-2酪氨酸磷酸化分别减少60%和40%。IL-6对这些蛋白质的质量没有影响。IL-6还降低了依赖再摄食的葡糖激酶基因的诱导量，降幅接近40%。胰岛素耐量测试显示胰岛素敏感性降低。与肝脏胰岛素受体信号转导相反，IL-6暴露5天不能抑制骨骼肌胰岛素受体信号转导。这些数据表明，慢性IL-6治疗选择性地损害了体内的肝脏胰岛素信号，进一步支持了IL-6在肥胖肝脏胰岛素抵抗中的作用。
Interleukin (IL)-6 is one of several proinflammatory cytokines associated with the insulin resistance of obesity and type 2 diabetes. There is, however, little direct evidence in vivo for a causative role of IL-6 in insulin resistance. Here, a 5-day constant subcutaneous infusion of hIL-6 before portal vein insulin challenge resulted in impairment of early insulin receptor signaling in the liver of mice. Importantly, the sixfold elevation of IL-6 attained with constant infusion was similar to levels reached in obesity. Consistent with an hepatic response to IL-6, STAT3 phosphorylation was increased in livers of IL-6-treated mice at 5 days. Chronic infusion of IL-6 also reduced hepatic insulin receptor autophosphorylation by 60% and tyrosine phosphorylation of insulin receptor substrates-1 and -2 by 60 and 40%, respectively. IL-6 had no effect on the mass of these proteins. IL-6 also decreased refeeding-dependent glucokinase mRNA induction by similar to40%. Insulin tolerance tests revealed reduced insulin sensitivity. In contrast to hepatic insulin receptor signal transduction, 5-day IL-6 exposure failed to suppress skeletal muscle insulin receptor signal transduction. These data suggest that chronic IL-6 treatment selectively impairs hepatic insulin signaling in vivo, further supporting a role for IL-6 in hepatic insulin resistance of obesity.