| Project/Area Number |
08457259
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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 |
内分泌・代謝学
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| Research Institution | University of Tokyo |
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Principal Investigator |
TOBE Kazuyuki University of Tokyo, Assistant, 医学部・附属病院, 助手 (30251242)
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| Co-Investigator(Kenkyū-buntansha) |
UEKI Kohjiroh University of Tokyo, Medical staff, 医学部・附属病院, 医員
KABURAGI Yasushi University of Tokyo, Medical staff, 医学部・附属病院, 医員
TAMEMOTO Hiroyuki University of Tokyo, Medical staff, 医学部・附属病院, 医員
HONDA Ritsuko University of Tokyo, Medical staff, 医学部・附属病院, 医員
KADOWAKI Takashi University of Tokyo, Lecturer, 医学部・附属病院, 講師 (30185889)
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| Project Period (FY) |
1996 – 1997
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| Project Status |
Completed (Fiscal Year 1997)
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| Budget Amount *help |
¥7,700,000 (Direct Cost: ¥7,700,000)
Fiscal Year 1997: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1996: ¥6,200,000 (Direct Cost: ¥6,200,000)
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| Keywords | insulin action / inculin receptor / insulin resistance / insulin receptor substrate / IRS-1 deficient mice / 糖尿病 / IRS-1欠損マウス / インスリン受容体基質1,2 / 欠損マウス |
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| Research Abstract |
Insulin receptor subustrate-1(IRS-1) is the major substrate of insulin receptor and IGF-l receptor tyrosine kinases. Tyrosine-phosphorylated IRS-1 binds the 85K subunit of phosphatidylinositol 3-kinase which may be involved in the translocation of glucose transporters and the abundant src homology protein (ASH) / Grb2 which may be involved in activationn of p2l* and MAP kinase cascade. To clarify the physiological roles of IRS-1 in vivo, we made mice with a targeted disruption of the IRS-1 gene locus. Mice homozygous for targeted disruption of the IRS-I gene were born alive but were retarded in embryonal and postnatal growth. They also had resistance to the glucose-lowering effects of insulin. These data suggest the existence of both IRS-1-dependent and IRS-1-independent pathways for signal transduction of insulin and IGF_s (Tmemoto et al., Nature 372 : 182-186, 1994). We have examined the insulin-stimulated tyrosine-phosphorylated proteins in livers of wild type and IRS-1-deficient mi
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ce. Tyrosine phosphorylation of an 190-kDa protein (ppl9O) by insulin was significantly stimulated in livers of IRS-1-deftcient mice, which was weakly observed in wild type mice in addition to IRS-1. We also demonstrated that pp190 was immunologically distinct from IRS-1 and was associated with both the 85-kDa subunit of phosphatidylinositol 3-kinase and the Grb2/Ash molecule as IRS-1. We identified pp190 as a novel substrate for insulin receptor kinase (IRS-2), which can bind both PI3-kinase and Ash/Grb2, and whose tyrosine phosphorylation is specifically induced in IRS-1-deficient mice. These data suggested that pp19O may play some physiological roles in insulin's signal transduction ; furthermore, induction of tyrosine phosphorylation of pp19O may be one of the compensatory mechanisms that substitute for IRS-1 in IRS-1-deficient mice (Tobe et al., I.Biob Chem. 270 : 5698-5701, 1995). We further investigated the roles of IRS-1 and IRS-2 in the biological actions in the physiological target organs of insulin by comparing the effects of insulin in wild-type and IRS-1-deficient mice. In muscles from IRS-1-deficient mice, the responses to insulin-induced P13-kinase activation, glucose transport, p70 S6 kinase and MAP kinase activation. mRNA translation, and protein synthesis were significantly impaired compared with those in wild-type mice. Insulin-induced protein synthesis was both wortmannin sensitive and insensitive in wild-type and IRS-I-deficient mice. However, in another target organ, the liver, the responses to insulin-induced P13-kinase and MAP kinase activation were not significantly reduced. The amount of tyrosine-phosphorylated IRS-2 (in IRS-1-deficient mice) was roughly equal to that of IRS-1 (in wild-type mice) in the liver, whereas it was only 20 to 30% of that of IRS-1 in the muscles. In counclusion, (i) IRS-1 plays central roles in two major biological actions of insulin in muscles, glucose transport and protein synthesis ; (ii) the insulin resistance Less
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