Chromium activates glucose transporter 4 trafficking and enhances insulin-stimulated glucose transport in 3T3-L1 adipocytes via a cholesterol-dependent mechanism
Chromium activates glucose transporter 4 trafficking and enhances insulin-stimulated glucose transport in 3T3-L1 adipocytes via a cholesterol-dependent mechanism
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DOI：
10.1210/me.2005-0255
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发表时间：
2006-04-01
影响因子：
--
通讯作者：
Elmendorf, JS
中科院分区：
文献类型：
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作者：
Chen, GL;Liu, P;Elmendorf, JS
有证据表明，补充铬可以缓解与糖尿病相关的症状，如高血糖和脂质异常，但其分子机制尚不清楚。在这里，我们报道了氯化物（CrCl3）或吡啶酸盐（CrPic）形式的三价铬调动葡萄糖转运蛋白GLUT4到3T3-L1脂肪细胞的质膜。随着质膜GLUT4的增加，铬处理增强了胰岛素刺激的葡萄糖转运。相反，在没有胰岛素的情况下，铬动员的转运蛋白池不活跃。对表面myc标记的增强绿色荧光蛋白- glut4构建物的显微镜分析显示，铬诱导的含glut4的囊泡积聚发生在内细胞膜附近。在胰岛素中，这些转运蛋白被物理地整合到质膜中。铬对GLUT4易位的调节不涉及已知的胰岛素信号蛋白，如胰岛素受体、胰岛素受体底物-1、磷脂酰肌醇3-激酶和Akt。与报道的铬对增加膜流动性的影响一致，我们发现铬处理降低了质膜胆固醇。有趣的是，胆固醇添加回质膜阻止了铬对GLUT4动员和胰岛素刺激的葡萄糖运输的有益作用。此外，在甲基- β -环糊精预处理的细胞中，铬的作用不存在，这些细胞已经显示出质膜胆固醇降低和GLUT4易位增加。总之，这些数据揭示了铬可能增强GLUT4运输和胰岛素刺激的葡萄糖运输的新机制。此外，这些细胞水平的发现与体内观察结果一致，即补充铬后葡萄糖耐量改善，循环胆固醇水平降低。
Evidence suggests that chromium supplementation may alleviate symptoms associated with diabetes, such as high blood glucose and lipid abnormalities, yet a molecular mechanism remains unclear. Here, we report that trivalent chromium in the chloride (CrCl3) or picolinate (CrPic) salt forms mobilize the glucose transporter, GLUT4, to the plasma membrane in 3T3-L1 adipocytes. Concomitant with an increase in GLUT4 at the plasma membrane, insulin-stimulated glucose transport was enhanced by chromium treatment. In contrast, the chromium-mobilized pool of transporters was not active in the absence of insulin. Microscopic analysis of an exofacially Myc-tagged enhanced green fluorescent protein-GLUT4 construct revealed that the chromium-induced accumulation of GLUT4-containing vesicles occurred adjacent to the inner cell surface membrane. With insulin these transporters physically incorporated into the plasma membrane. Regulation of GLUT4 translocation by chromium did not involve known insulin signaling proteins such as the insulin receptor, insulin receptor substrate-1, phosphatidylinositol 3-kinase, and Akt. Consistent with a reported effect of chromium on increasing membrane fluidity, we found that chromium treatment decreased plasma membrane cholesterol. Interestingly, cholesterol add-back to the plasma membrane prevented the beneficial effect of chromium on both GLUT4 mobilization and insulin-stimulated glucose transport. Furthermore, chromium action was absent in methyl-beta-cyclodextrin-pretreated cells already displaying reduced plasma membrane cholesterol and increased GLUT4 translocation. Together, these data reveal a novel mechanism by which chromium may enhance GLUT4 trafficking and insulin-stimulated glucose transport. Moreover, these findings at the level of the cell are consistent with in vivo observations of improved glucose tolerance and decreased circulating cholesterol levels after chromium supplementation.