Rab5 activity regulates GLUT4 sorting into insulin-responsive and non-insulin-responsive endosomal compartments: a potential mechanism for development of insulin resistance.
Rab5 activity regulates GLUT4 sorting into insulin-responsive and non-insulin-responsive endosomal compartments: a potential mechanism for development of insulin resistance.
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DOI：
10.1210/en.2013-2148
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发表时间：
2014-06
期刊：
影响因子：
4.8
通讯作者：
K. L. Tessneer;R. M. Jackson;Beth A. Griesel;A. Olson
中科院分区：
文献类型：
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作者：
K. L. Tessneer;R. M. Jackson;Beth A. Griesel;A. Olson
葡萄糖转运蛋白亚型4（GLUT 4）是胰岛素响应性葡萄糖转运蛋白，介导脂肪和骨骼肌中的葡萄糖摄取。GLUT 4从细胞内储存区室向质膜的转位减少是外周胰岛素抵抗的原因。使用慢性高胰岛素血症（CHI）诱导的胰岛素抵抗和Rab 5突变体过表达的细胞模型，我们确定这些操作改变了GLUT 4的内体分选，从而有助于胰岛素抵抗的发展。我们发现CHI通过将GLUT 4保留在Rab 5活性依赖性隔室中诱导3 T3-L1脂肪细胞中的胰岛素抵抗，所述隔室不能与细胞表面平衡以响应胰岛素。此外，CHI介导的GLUT 4在该非胰岛素响应隔室中的保留损害了转铁蛋白受体（TfR）阳性和TfR阴性胰岛素响应储存隔室的填充。我们的数据表明，高胰岛素血症可能通过长期维持Rab 5活性依赖性内体途径中的GLUT 4并损害TfR阴性和TfR阳性胰岛素反应性GLUT 4库的形成来抑制GLUT 4。该模型表明，在脂肪组织中胰岛素抵抗葡萄糖转运的发展中的早期事件是改变GLUT 4的细胞内定位到当胰岛素水平长时间升高时不能有效地与细胞表面平衡的隔室。
Glucose transporter isoform 4 (GLUT4) is the insulin-responsive glucose transporter mediating glucose uptake in adipose and skeletal muscle. Reduced GLUT4 translocation from intracellular storage compartments to the plasma membrane is a cause of peripheral insulin resistance. Using a chronic hyperinsulinemia (CHI)-induced cell model of insulin resistance and Rab5 mutant overexpression, we determined these manipulations altered endosomal sorting of GLUT4, thus contributing to the development of insulin resistance. We found that CHI induced insulin resistance in 3T3-L1 adipocytes by retaining GLUT4 in a Rab5-activity-dependent compartment that is unable to equilibrate with the cell surface in response to insulin. Furthermore, CHI-mediated retention of GLUT4 in this non-insulin-responsive compartment impaired filling of the transferrin receptor (TfR)-positive and TfR-negative insulin-responsive storage compartments. Our data suggest that hyperinsulinemia may inhibit GLUT4 by chronically maintaining GLUT4 in the Rab5 activity-dependent endosomal pathway and impairing formation of the TfR-negative and TfR-positive insulin-responsive GLUT4 pools. This model suggests that an early event in the development of insulin-resistant glucose transport in adipose tissue is to alter the intracellular localization of GLUT4 to a compartment that does not efficiently equilibrate with the cell surface when insulin levels are elevated for prolonged periods of time.