Molecular mechanisms of Insulin signal transduction and diabetes mellitus

AKT底物160 kDa(AS160)是一种Rab GTPase激活蛋白(GAP)，最近被发现是葡萄糖转运蛋白4(GLUT4)易位的胰岛素信号通路的组成部分。我们和其他人之前报道，Galphaq蛋白偶联受体(GalphaqPCRs)的激活也刺激了几种细胞系中GLUT4的易位和葡萄糖的摄取。在这里，我们报道GalphaqPCRs的激活也促进了5‘-AMP激活的蛋白激酶(AMPK)对AS160的磷酸化。缺失AS160的大鼠3Y1细胞未表现出胰岛素诱导的GLUT4易位。稳定表达GLUT4的细胞可见GLUT4囊泡，主要分布在核周，较少出现在细胞表面。外源AS160表达后，细胞表面GLUT4减少，GLUT4囊泡重新分布于细胞质。尽管PMA或氟化钠诱导的GLUT4易位显著增加，但胰岛素不影响GLUT4易位。这些结果表明，AS160是胰岛素和GalphaqPCR激活介导的GLUT4在细胞内分布的共同调节因子。

Akt substrate of 160kDa (AS160) is a Rab GTPase activating protein (GAP) and was recently identified as a component of the insulin signaling pathway of glucose transporter type 4 (GLUT4) translocation. We and others, previously reported that the activation of Galphaq protein-coupled receptors (GalphaqPCRs) also stimulated GLUT4 translocation and glucose uptake in several cell lines. Here, we report that the activation of GalphaqPCRs also promoted phosphorylation of AS160 by the 5'-AMP activated proteinkinase (AMPK). Rat 3Y1 cells lacking AS160 did not show insulin-induced GLUT4 translocation. The cells stably expressing GLUT4 revealed GLUT4 vesicles that were mainly localized in the perinuclear region and less frequently on the cell surface. After expression of exogenous AS160, GLUT4 on the cell surface decreased and GLUT4 vesicles were redistributed throughout the cytoplasm. Although PMA-induced or sodium fluoride-induced GLUT4 translocation was significantly increased in these cells, insulin did not affect GLUT4 translocation. These results suggest that AS160 is a common regulator of insulin-and GalphaqPCR activation-mediated GLUT4 distribution in the cells.