Interleukin-6 induces cellular insulin resistance in hepatocytes
Interleukin-6 induces cellular insulin resistance in hepatocytes
复制标题
DOI：
10.2337/diabetes.51.12.3391
复制
发表时间：
2002-12-01
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：
Senn, JJ;Klover, PJ;Mooney, RA
白细胞介素（IL）-6是与胰岛素抵抗和2型糖尿病相关的几种促炎细胞因子之一。在这些条件下，已观察到循环IL-6升高2至3倍。尽管如此，很少有证据支持IL-6在介导胰岛素抵抗中的直接作用。在这里，我们提出的数据，IL-6可以抑制胰岛素受体（IR）的信号转导和胰岛素的作用，在原代小鼠肝细胞和人肝癌细胞系，HepG 2。这种抑制作用取决于IL-6暴露的持续时间，在HepG 2细胞和原代肝细胞中用IL-6预处理1-1.5 μ l时效果最大。IL-6作用的特征在于IR底物（IRS）-1的酪氨酸磷酸化降低和响应于生理胰岛素水平的磷脂酰肌醇3-激酶的p85亚基与IRS-1的缔合降低。此外，在介导胰岛素下游代谢作用中重要的Akt的胰岛素依赖性活化被IL-6处理显著抑制。最后，原代肝细胞与IL-6预孵育1.5小时可抑制75%的胰岛素诱导的糖原合成。这些数据表明，IL-6在原代肝细胞和HepG 2细胞系的细胞水平上在胰岛素抵抗中起直接作用，并可能导致胰岛素抵抗和2型糖尿病。
Interleukin (IL)-6 is one of several proinflammatory cytokines that have been associated with insulin resistance and type 2 diabetes. A two- to threefold elevation of circulating IL-6 has been observed in these conditions. Nonetheless, little evidence supports a direct role for IL-6 in mediating insulin resistance. Here, we present data that IL-6 can inhibit insulin receptor (IR) signal transduction and insulin action in both primary mouse hepatocytes and the human hepatocarcinoma cell line, HepG2. This inhibition depends on duration of IL-6 exposure, with a maximum effect at 1-1.5 It of pretreatment with IL-6 in both HepG2 cells and primary hepatocytes. The IL-6 effect is characterized by a decreased tyrosine phosphorylation of IR substrate (IRS)-1 and decreased association of the p85 subunit of phosphatidylinositol 3-kinase with IRS-1 in response to physiologic insulin levels. In addition, insulin-dependent activation of Akt, important in mediating insulin's downstream metabolic actions, is markedly inhibited by IL-6 treatment. Finally, a 1.5-h preincubation of primary hepatocytes with IL-6 inhibits insulin-induced glycogen synthesis by 75%. These data suggest that IL-6 plays a direct role in insulin resistance at the cellular level in both primary hepatocytes and HepG2 cell lines and may contribute to insulin resistance and type 2 diabetes.