Molecular mechanisms of insulin signal transduction and diabetes mellitus
| Project/Area Number |
18390104
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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 |
Pathological 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 (00112227)
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| Co-Investigator(Kenkyū-buntansha) |
UCHIYAMA Keiji The University of Tokushima, Institute for Enzyme Research, Associate Professor (60294039)
YUASA Tomoyuki The University of Tokushima, Institute for Enzyme Research, Assistant Professor (50304556)
NAGAYA Hisao The University of Tokushima, Institute for Enzyme Research, Assistant Professor (60464343)
OGURA Yuko The University of Tokushima, Institute for Enzyme Research, COE Researcher (90464354)
小畑 利之 徳島大学, 分子酵素学研究センター, 助教授 (40325296)
勅使河原 匡 徳島大学, 分子酵素学研究センター, COE研究員 (40403737)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥16,830,000 (Direct Cost: ¥14,700,000、Indirect Cost: ¥2,130,000)
Fiscal Year 2007: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
Fiscal Year 2006: ¥7,600,000 (Direct Cost: ¥7,600,000)
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| Keywords | insulin receptor / soluble ectodomain / diabetes / signal transduction / GLUT4 translocation / AS160 / Gq coupled receptor / インスリン |
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| Research Abstract |
The ectodomains of receptors for several cytokines and growth factors have been found to circulate in plasma. Thus, the existence of soluble IR in human serum has been suspected.
Furthermore, transgenic mice secreting soluble IRα into the plasma showed chronic hyperglycemia. Here, we established novel enzyme-linked immunosorbent assay (ELISA) systems to measure both the ectodomain (α-subunit and a part of β-subunit) of IR and full length of IR.
With these ELISA systems, we report that soluble hlRα with parts of extracellular region of hIRβ, but not as a whole IR or with intact hlRβ, is present in human plasma and that its plasma level is elevated in patients with elevated blood glucose. The ectodomain of IR may be cleaved, at least in part, by hyperglycemic state-associated mechanisms.
We and others previously reported that the activation of Gaq protein- coupled receptors (GaqPCRs) also stimulates GLUT4 translocation and glucose uptake in several cell lines. Here, we report that the activation of GaqPCRs also promoted the phosphorylation of AS160, Akt substrate of 160 KDa which is Rab GTPase activating protein (GAP), by 5'-AMP activated protein kinase (AMPK). The suppression of AS160 phosphorylation by AMPKα1 subunit knockdown using siRNA promoted GLUT4 vesicle retention at intracellular compartments, but did not affect a fold increase of the Gaq- stimulated GLUT4 translocation. These results suggest that AS160 is a common mediator of the GLUT4 vesicle trafficking stimulated by insulin and by the activation of GaqPCR. The AS160 regulates the intracellular distribution of the GLUT4 vesicles and its retention inside the cells.
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Report
(3 results)
Research Products
(13 results)
