Endotoxin-induced alterations in insulin-stimulated phosphorylation of insulin receptor, IRS-1, and MAP kinase in skeletal muscle
Endotoxin-induced alterations in insulin-stimulated phosphorylation of insulin receptor, IRS-1, and MAP kinase in skeletal muscle
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DOI：
10.1097/00024382-199609000-00002
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发表时间：
1996-09-01
期刊：
影响因子：
3.1
通讯作者：
Lang, CH
中科院分区：
文献类型：
--
作者：
Fan, J;Li, YH;Lang, CH
脓毒症和内毒素(LPS)可损害胰岛素介导的骨骼肌葡萄糖摄取。然而，导致这一缺陷的细胞内机制还没有完全确定。本研究的目的是确定内毒素是否改变了骨骼肌中胰岛素受体或(或)信号通路的特定元件。体内注射大肠杆菌脂多糖可使正常血糖水平的高胰岛素血症大鼠体内葡萄糖代谢减少44%，这主要是由于糖原合成速率降低所致。Scatchard分析表明，对照组和内毒素处理组大鼠肌肉中高亲和力胰岛素结合位点的数量和亲和力相似。Western印迹分析显示，在基础状态下，对照组和内毒素组大鼠的总IR、磷酸化IR、胰岛素受体底物(IRS)-1和丝裂原活化蛋白(MAP)激酶的水平无显著差异。在对照动物中，静脉注射最大刺激量的胰岛素后2分钟获得的肌肉显示，磷酸化IR(接近5倍)、IRS-1(接近10倍)和MAP激酶(接近10倍)的数量显著增加。胰岛素刺激的IR、IRS-1和MAP激酶的磷酸化水平在内毒素处理的大鼠显著降低(分别为75%、90%和78%)。然而，在高胰岛素状态下，这些蛋白质的总丰度并没有随之减少。这些数据表明，内毒素改变了胰岛素信号转导通路的多个步骤，但不改变骨骼肌中胰岛素的结合，这可能介导了观察到的葡萄糖摄取障碍。
Sepsis and endotoxin (LPS) have been demonstrated to impair insulin-mediated glucose uptake in skeletal muscle. However, the intracellular mechanism responsible for this defect is not fully defined. The purpose of the present study was to determine whether specific elements of the insulin receptor OR) signaling pathway in skeletal muscle are altered by LPS. In vivo injection of Escherichia coli LPS resulted in a 44% reduction in whole body glucose disposal under euglycemic hyperinsulinemic conditions, which was largely accounted for by a decreased rate of glycogen synthesis. Scatchard analysis indicated that the number and affinity of the high-affinity insulin binding sites in muscle were similar between control and LPS-treated rats. Western blot analysis indicated that under basal conditions, the levels of total and phosphorylated IR, insulin receptor substrate (IRS)-1, and mitogen-activated protein (MAP) kinase were not significantly different between control and endotoxic rats. In control animals, muscle obtained 2 min after intravenous injection of a maximally stimulating dose of insulin demonstrated a marked increase in the amount of phosphorylated IR (similar to 5-fold), IRS-1 (similar to 10-fold), and MAP kinase (similar to 10-fold). insulin-stimulated phosphorylation of IR, IRS-1, and MAP kinase was markedly diminished (similar to 75%, 90%, and 78%, respectively) in LPS-treated rats. However, there was no concomitant reduction in the total abundance of these proteins under hyperinsulinemic conditions. These data demonstrate that LPS alters multiple steps in the insulin signal transduction pathway, but not insulin binding, in skeletal muscle that may mediate the observed impairment in glucose uptake.