2001 Fiscal Year Final Research Report Summary
Molecular mechanisms of insulin signal transduction and diabetas mellitus
| Project/Area Number |
12470027
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General medical chemistry
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| Research Institution | The University of Tokushima |
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Principal Investigator |
EBINA Yousuke The University of Tokushima, Institute for Enzyme Research, Professor, 分子酵素学研究センター, 教授 (00112227)
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| Co-Investigator(Kenkyū-buntansha) |
OBATA Toshiyuki The University of Tokushima, Institute for Enzyme Research, Research Associate, 分子酵素学研究センター, 助手 (40325296)
YUASA Tomoyuki The University of Tokushima, Institute for Enzyme Research, Research Associate, 分子酵素学研究センター, 助手 (50304556)
KISHI Kazuhiro The University of Tokushima, Institute for Enzyme Research, Associate Professor, 分子酵素学研究センター, 助教授 (70284320)
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| Project Period (FY) |
2000 – 2001
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| Keywords | Insulin signal translocation / Type 2 diabetes / GLUT4 translocation / glucose uptake / Gq / AMP-activated protein kinase |
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| Research Abstract |
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
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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
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