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Molecular mechanisms of insulin signal transduction and diabetas mellitus

胰岛素信号转导与糖尿病的分子机制

基本信息

批准号：
12470027
负责人：
EBINA Yousuke
金额：
$ 9.15万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470027/
关键词：
Insulin signal translocation Type 2 diabetes GLUT4 translocation glucose uptake Gq AMP-activated protein kinase GLUT4 Gq インスリン三量体GタンパクGq

项目摘要

GTP γ S induces the translocation of glucose transporter type 4 (GLUT4) from an intracellular pool to the cell surface and increases glucose uptake in adipocytes. The GTP-binding protein(s) responsible for the translocation has remained to be identified. We obtained evidence that the activation of receptor-coupled Gq triggered GLUT4 translocation in cells, independently of insulin signaling pathway(s). Norepinephrine triggered GLUT4 translocation in cells expressing the Gq-coupled alphal -adrenergic receptor. The norepinephrine-stimulated GLUT4 translocation and glucose uptake via Gq may possibly contribute to the fuel supply required for thermogenesis in brown adipocytes and for the enhanced contractility in cardiomyocytes, both of which have an abundant endogenous GLUT4.Physical exercise induces translocation of GLUT4 from an intracellular pool to the cell surface in skeletal muscles and increases glucose uptake via an insulin-independent pathway. However, the molecular mechanism rem … More ains to be identified. Some studies have suggested that bradykinin is locally released from contracting muscles and may be responsible for GLUT4 translocation and the increase of glucose transport in skeletal muscles. We found that bradykinin directly triggered GLUT4 translocation and increased the rate of glucose uptake in a dose-dependent manner in these cells. Bradykinin is probably one of the factors responsible for exercise-stimulated glucose uptake in skeletal muscles.The AMP-activated protein kinase (AMPK) functions as a metabolic sensor that monitors cellular AMP and ATP levels. Norepinephrine and bradykinin also activated AMPK α 1 in cells expressing G(q)-coupled α 1b-adrenergic receptor and bradykinin receptor, respectively. AMPK α 1 is activated specifically by stimulation of G(q)-coupled receptors. G(q)-coupled receptors transmit the signal for GLUT4 translocation and glucose uptake through an insulin-independent pathway. However, direct activation of AMPK α 1 with treatment of 5-aminoimidazole-4-carboxamide- 1 -beta-d-ribofuranoside did not trigger GLUT4 translocation. Thus, activation of AMPK α 1 via G(q) is not sufficient to trigger GLUT4 translocation or stimulate glucose uptake. Less

天冬氨酸转运蛋白γS诱导葡萄糖转运蛋白4(GLUT4)从细胞内池转移到细胞表面，增加脂肪细胞对葡萄糖的摄取。负责易位的GTP结合蛋白(S)仍未确定。我们获得的证据表明，受体偶联GQ的激活触发了细胞内GLUT4的易位，而不依赖于胰岛素信号转导途径(S)。去甲肾上腺素在表达GQ-α-肾上腺素能受体的细胞中触发GLUT4易位。去甲肾上腺素刺激的GLUT4移位和通过GQ摄取葡萄糖可能有助于棕色脂肪细胞产热所需的燃料供应和心肌细胞收缩能力的增强，两者都含有丰富的内源性GLUT4，体育运动诱导骨骼肌GLUT4从细胞内池转移到细胞表面，并通过不依赖胰岛素的途径增加葡萄糖摄取。然而，Rem…的分子机制还有更多的AN有待确认。一些研究表明，缓激肽是从收缩的肌肉中局部释放出来的，可能与GLUT4易位和骨骼肌葡萄糖转运增加有关。我们发现缓激肽直接触发了GLUT4的易位，并以剂量依赖的方式增加了这些细胞的葡萄糖摄取率。缓激肽可能是运动刺激骨骼肌摄取葡萄糖的因素之一，AMP激活的蛋白激酶(AMPK)作为代谢传感器监测细胞内AMP和ATP的水平。去甲肾上腺素和缓激肽也分别在表达G(Q)偶联α1b受体和缓激肽受体的细胞中激活AMPKα1。AMPKα1通过刺激G(Q)偶联受体而被特异性激活。G(Q)偶联受体通过不依赖胰岛素的途径传递GLUT4易位和葡萄糖摄取的信号。然而，5-氨基咪唑-4-甲酰胺-1-β-d-呋喃核苷直接激活AMPKGLUT1并不触发α易位。因此，通过G(Q)激活AMPKGLUT1不足以触发α易位或刺激葡萄糖摄取。较少