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Molecular mechanisms of insulin signal transduction and diabetes mellitus

Research Project

Project/Area Number 08457050
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Pathological medical chemistry
Research InstitutionThe University of Tokushima

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)

Co-Investigator(Kenkyū-buntansha) KISHI Kazuhiro  The University of Tokushima, Institute for Enzyme Research, Research Associate, 分子酵素学研究センター, 助手 (70284320)
HAYASHI Hideki  The University of Tokushima, Institute for Enzyme Research, Associate Professor, 分子酵素学研究センター, 助教授 (10218589)
Project Period (FY) 1996 – 1997
Project Status Completed (Fiscal Year 1997)
Budget Amount *help
¥7,800,000 (Direct Cost: ¥7,800,000)
Fiscal Year 1997: ¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 1996: ¥5,400,000 (Direct Cost: ¥5,400,000)
KeywordsInsulin action / glucosetransporter / Diabetes / インスリン / GLUT4 / トランスロケーション / PI3-キナーゼ / グルコース取り込み
Research Abstract

1) Rat 3Y1 cells, which have endogenous insulin-like growth factor-1 receptor (IGF-1-R) and insulin receptor substrate-2 (IRS-2), but lack both insulin receptor (IR) and IRS-1, exhibit no insulin effects. To investigate the role of IR and RIS-1 in insulin effects, we reconstituted the insulin signaling pathways in the cells. The expression of IRS-1 in 3Y1-GLUT4myc・IR cells leads to the stimulation of glycogen synthesis but no to the GLUT4myc translocation in response to insulin, although the treatment of NaF or PMA triggers GLUT4myc translocation in the cells. These results indicate that, in 3Y1 cells in response to insulin, i) IRS-1 is necessary for glycogen synthesis, not essential for DNA synthesis, Akt phosphorylation and membrane ruffling, ii) the accumulation of PI-3,4,5-P_3 is required for Akt phosphorylation and membrane reffling, iii) the accumulation of PI-3,4,5-P_3 and activation of Akt are not sufficient for glycogen synthesis and GLUT4 translocation.
2) Translocation of the type 4 glucose transporter (GLUT4) to the cell surface from an intracellular pool is the major mechanism of insulin-stimulated glucose uptake in insulin-target cells. We developed a highly sensitive and quantitative method to detect GLUT4 immunologically on the surface of intact cells, using c-myc epitope-tagged GLUT4 (GLUT4myc). Since GLUT1 and GLUT4 have different intracellular distributions and different degrees of insulin translocation, we examined the domains of GLUT4, using c-myc epitope-tagged chimeric glucose transporters between these two isoforms. The result intracellular loop and cytoplasmic C-terminal region of GLUT4 have independent intracellular targeting signals, (2) these sequences for intracellular targeting of GLUT4 were not sufficient to determine GLUT4 translocation in response to insulin, and (3) the N-terminal half of GLUT4 devoid both of cytoplasmic N-terminus and of middle intracellular loop seems to be necessary for insulin-stimulated GLUT4 translocation.

Report

(3 results)
  • 1997 Annual Research Report   Final Research Report Summary
  • 1996 Annual Research Report
  • Research Products

    (15 results)

All Other

All Publications (15 results)

  • [Publications] Kazuhiro Kishi, Yousuke Ebina, et al.: "Bradykinin directly triggers GLUT4 translocation via an insulin-independent pathway" Diabetes. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Nitzan Kozlovsky, Yousuke Ebina, et al.: "Transcriptional activation of the Glutl gene in response to oxidative stress in L6 myotubes" J.Biol.Chem.272. 33367-33372 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Lihong Wang, Yousuke Ebina, et al.: "Hyperinsulinemia but no diabetes in transgenic mice homozygously expressing the tyrosine Kinase-deficient human insulin receptor" Biochem.Biophys.Res.Commun.240. 446-451 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kazuhiro Kishi, Yousuke Ebina, et al.: "Gq-coupled receptors transmit the signal for GLUT4 translocation via an insulin-independent pathway" J.Biol.Chem.271. 26561-26568 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kishi K., Ebina Y.et.al.: "Bradykinin directly triggers GLUT4 translocation via an insulin-independent pathway" Diabetes. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kozlovsky N., Ebina Y.et.al.: "Transcriptional activation of the glut1 gene in response to oxidative stress in L6 myotubes" J.Biol.Chem.272. 33367-33372 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Wang L., Ebina Y.et.al.: "Hyperinsulinemia but no diabetes in transgenic mice homozygously expressing the tyrosine kinase-deficient human insulin receptor" Biochem.Biophys.Res.Commun.240. 446-451 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kishi K., Ebina Y.et.al.: "Gq-coupled receptors transmit the signal for GLUT4 translocation via an insulin-independent pathway" J.Biol.Chem.271. 26561-26568 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kazuhiro Kishi, Yousuke Ebina, et al.: "Bradykinin directly triggers GLUT4 translocation via an insulin-independent pathway" Diabetes. (in press).

    • Related Report
      1997 Annual Research Report
  • [Publications] Nitzan Kozlovsky, Yousuke Ebina, et al.: "Transcriptional activation of the Glutl gene in response to oxidative stress in L6 myotubes" J.Biol.Chem.272. 33367-33372 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Lihong Wang, Yousuke Ebina, et al.: "Hyperinsulinemia but no diabetes in transgenic mice homozygously expressing the tyrosine kinase-deficient human insulin receptor" Biochem.Biophys.Res.Commun.240. 446-451 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kazuhiro Kishi, Yousuke Ebina, et al.: "Gq-coupled receptors transmit the signal for GLUT4 translocation via an insulin-independent pathway" J.Biol.Chem.271. 26561-26568 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kishi,K.,Ebina,Y.et al.: "Gq-coupled receptors transmit the signal for GLUT4 translocation via an insulin-independent pathway" J.Biol.Chem.271. 26561-26568 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Todaka,M.,Ebina.Y.et al.: "Roles of insulin,guanosine 5′-〔γ-thio〕triphosphate and phorbol 12-myristate 13-acetate in signaling pathways of GLUT4 translocation" Biochem.J.315. 875-882 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 蛯名洋介: "化学と生物「インスリンによる細胞内へのグルコース取り込み促進機構」" 日本農芸化学会編集 学会出版センター発行, 2 (1996)

    • Related Report
      1996 Annual Research Report

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Published: 1996-04-01   Modified: 2016-04-21  

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