Dual role of interleukin-6 in regulating insulin sensitivity in murine skeletal muscle.
Dual role of interleukin-6 in regulating insulin sensitivity in murine skeletal muscle.
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作者：
Nieto-Vazquez I;Fernández-Veledo S;de Alvaro C;Lorenzo M
细胞因子在各种胰岛素抵抗状态下升高，包括2型糖尿病和肥胖症，尽管白细胞介素-6（IL-6）在诱导这些疾病中的作用存在争议。研究设计和方法-我们分析了IL-6对小鼠原代肌细胞、骨骼肌细胞系和小鼠（野生型和蛋白酪氨酸磷酸酶1B [PTP1B]缺陷型）胰岛素作用的影响。IL-6本身通过激活丝氨酸/苏氨酸蛋白激酶11（LKB 1）/AMP活化蛋白激酶/160 kDa蛋白激酶B底物（AS 160）途径增加葡萄糖摄取。当肌管和小鼠暴露于该细胞因子时，观察到对胰岛素作用的双重效应：与短期胰岛素相加（增加葡萄糖摄取和全身胰岛素敏感性），但长期暴露产生胰岛素抵抗（受损的GLUT 4向质膜的易位和胰岛素受体底物1 [IRS-1]水平的胰岛素信号传导缺陷）。在IL-6诱导的胰岛素抵抗中有三种机制：c-Jun NH2-末端激酶1/2（JNK1/2）的激活，细胞因子信号转导抑制因子3（socs3）mRNA的积累，以及PTP1B活性的增加。因此，用小干扰RNA或化学抑制剂沉默JNK1/2会损害IRS-1（Ser307）的磷酸化，恢复胰岛素信号传导，并使胰岛素诱导的肌管葡萄糖摄取正常化。当使用药理学方法时，肝X受体激动剂通过下调socs3和ptp1b基因表达来克服IL-6诱导的胰岛素抵抗。最后，PTP1B的缺乏在体外和体内骨骼肌中赋予针对IL-6诱导的胰岛素抵抗的保护，与在成年雄性小鼠中葡萄糖和胰岛素耐受性试验中观察到的针对IL-6高血糖效应的保护一致。结论：这些发现表明IL-6在胰岛素抵抗发病机制中的重要作用，并进一步暗示PTP1B是治疗2型糖尿病的潜在治疗靶点。
OBJECTIVE—Cytokines are elevated in various insulin-resistant states, including type 2 diabetes and obesity, although the contribution of interleukin-6 (IL-6) in the induction of these diseases is controversial. RESEARCH DESIGN AND METHODS—We analyzed the impact of IL-6 on insulin action in murine primary myocytes, skeletal muscle cell lines, and mice (wild type and protein-tyrosine phosphatase 1B [PTP1B] deficient). RESULTS—IL-6 per se increased glucose uptake by activating serine/threonine protein kinase 11 (LKB1)/AMP-activated protein kinase/protein kinase B substrate of 160 kDa (AS160) pathway. A dual effect on insulin action was observed when myotubes and mice were exposed to this cytokine: additive with short-term insulin (increased glucose uptake and systemic insulin sensitivity) but chronic exposure produced insulin resistance (impaired GLUT4 translocation to plasma membrane and defects in insulin signaling at the insulin receptor substrate 1 [IRS-1] level). Three mechanisms seem to operate in IL-6–induced insulin resistance: activation of c-Jun NH2-terminal kinase 1/2 (JNK1/2), accumulation of suppressor of cytokine signaling 3 (socs3) mRNA, and an increase in PTP1B activity. Accordingly, silencing JNK1/2 with either small interfering RNA or chemical inhibitors impaired phosphorylation of IRS-1 (Ser307), restored insulin signaling, and normalized insulin-induced glucose uptake in myotubes. When using a pharmacological approach, liver X receptor agonists overcome IL-6–induced insulin resistance by producing downregulation of socs3 and ptp1b gene expression. Finally, the lack of PTP1B confers protection against IL-6–induced insulin resistance in skeletal muscle in vitro and in vivo, in agreement with the protection against the IL-6 hyperglycemic effect observed on glucose and insulin tolerance tests in adult male mice. CONCLUSIONS—These findings indicate the important role of IL-6 in the pathogenesis of insulin resistance and further implicate PTP1B as a potential therapeutic target in the treatment of type 2 diabetes.
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