Loss of cortical actin filaments in insulin-resistant skeletal muscle cells impairs GLUT4 vesicle trafficking and glucose transport
Loss of cortical actin filaments in insulin-resistant skeletal muscle cells impairs GLUT4 vesicle trafficking and glucose transport
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DOI：
10.1152/ajpcell.00107.2006
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发表时间：
2006-11-01
影响因子：
5.5
通讯作者：
Elmendorf, Jeffrey S.
中科院分区：
文献类型：
--
作者：
McCarthy, Alicia M.;Spisak, Kristen O.;Elmendorf, Jeffrey S.
研究表明，皮质细丝肌动蛋白(F-肌动蛋白)在胰岛素调节的骨骼肌葡萄糖摄取中起着重要作用。在这里，我们测试了F-肌动蛋白的扰动是否导致了高胰岛素血症引起的胰岛素反应性受损。在稳定表达GLUT4并带有表位标签的L6肌管中，急性胰岛素刺激(20min，100 nM)使GLUT4myc转位和葡萄糖摄取增加近2倍。相反，在培养液中加入5 NM胰岛素12小时所引起的高胰岛素血症状态降低了胰岛素刺激这些过程的能力。胰岛素信号的缺陷并不能很容易地解释观察到的干扰。相反，高胰岛素血症降低了皮质F-肌动蛋白。这伴随着细胞膜磷脂酰肌醇4，5-二磷酸(PIP2)的丢失，PIP2是一种参与细胞骨架调节的脂质。高胰岛素细胞质膜PIP2的修复恢复了F-肌动蛋白和胰岛素的反应性。与高胰岛素状态对皮质F-肌动蛋白结构产生负面影响的体外观察结果一致，胰岛素抵抗的高胰岛素血症Zucker肥胖大鼠的外周骨骼肌与瘦肉型胰岛素敏感仔鼠肌肉中的F-肌动蛋白结构丢失相似。我们认为，胰岛素诱导的骨骼肌胰岛素抵抗的一个组成部分涉及PIP2/F-肌动蛋白结构的缺陷，PIP2/F-肌动蛋白结构对于胰岛素调节的葡萄糖运输至关重要。
Study has demonstrated an essential role of cortical filamentous actin (F-actin) in insulin-regulated glucose uptake by skeletal muscle. Here, we tested whether perturbations in F-actin contributed to impaired insulin responsiveness provoked by hyperinsulinemia. In L6 myotubes stably expressing GLUT4 that carries an exofacial myc-epitope tag, acute insulin stimulation (20 min, 100 nM) increased GLUT4myc translocation and glucose uptake by similar to 2-fold. In contrast, a hyperin-sulinemic state, induced by inclusion of 5 nM insulin in the medium for 12 h decreased the ability of insulin to stimulate these processes. Defects in insulin signaling did not readily account for the observed disruption. In contrast, hyperinsulinemia reduced cortical F-actin. This occurred concomitant with a loss of plasma membrane phosphatidylinositol 4,5-bisphosphate (PIP2), a lipid involved in cytoskeletal regulation. Restoration of plasma membrane PIP2 in hyperinsulinemic cells restored F-actin and insulin responsiveness. Consistent with these in vitro observations suggesting that the hyperinsulinemic state negatively affects cortical F-actin structure, epitrochlearis skeletal muscle from insulin-resistant hyperinsulinemic Zucker fatty rats displayed a similar loss of F-actin structure compared with that in muscle from lean insulin-sensitive littermates. We propose that a component of insulin-induced insulin resistance in skeletal muscle involves defects in PIP2/F-actin structure essential for insulin-regulated glucose transport.