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性ホルモンは、変異インスリン分子の膵β細胞毒性に影響するか?

Research Project

Project/Area Number 14657268
Research Category

Grant-in-Aid for Exploratory Research

Allocation TypeSingle-year Grants
Research Field Metabolomics
Research InstitutionGunma University

Principal Investigator

泉 哲郎  群馬大学, 生体調節研究所, 教授 (00212952)

Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2003: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2002: ¥1,600,000 (Direct Cost: ¥1,600,000)
Keywords糖尿病 / インスリン分泌 / インスリン遺伝子異常 / 膵β細胞 / 性ホルモン
Research Abstract

申請者は、常染色体優性遺伝形式を示す糖尿病モデルModyマウス(別名Akitaマウス)の原因遺伝子が、インスリン2遺伝子システイン残基の点突然変異によることを過去に見出している。折りたたみ不全の変異プロインスリンは、小胞体品質管理機構によりゴルジ装置以降へ輸送されず、インスリン分泌不全が起こる。変異プロインスリン発現は、構成性に分泌される分泌型アルカリフォスファターゼの細胞内輸送を阻害し、分泌顆粒の縮小、小胞体様オルガネラ内腔拡大、ミトコンドリア・ライソゾームの膨潤などの膵β細胞変性を引き起こした。以上の所見は、変異プロインスリンの細胞内蓄積が、非特異的にオルガネラ機能不全を引き起こし、共存する正常インスリンの分泌不全もきたしていることを示唆している。その結果Modyマウスは強い耐糖能障害を示すが、その程度は、オスに比しメスでは軽度である。これまでの交配実験結果より、この耐糖能の性差は、X、Y染色体遺伝子、ミトコンドリア遺伝子、インプリント遺伝子などの遺伝情報の違いによるものではなく、性染色体構成の差に依存し、性ホルモンの影響が最も考えられた。しかしModyマウスをSPF、conventional環境下で飼育・比較したところ、耐糖能の性差がSPF環境下で大きく減弱することを認め、性ホルモン以外の要因も考えられた。現在、本マウスの膵β細胞傷害過程を、性ホルモンおよび他の環境要因がどのように修飾するかを研究している。

Report

(2 results)
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • Research Products

    (14 results)

All Other

All Publications (14 results)

  • [Publications] Izumi T., et al.: "Dominant negative pathogenesis by mutant proinsulin in the Akita diabetic mouse."Diabetes. 52・2. 409-416 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yaguchi M., et al.: "Neurological study of C57BL/6Akita mouse, type 2 diabetic model : enhanced expression of aB-crystallin in oligodendrocytes."Neuropathology. 23・1. 44-50 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Zhang B., et al.: "Parathyroid hormone-related protein induces insulin expression through activation of MAP kinase-specific phosphatase-1 that dephosphorylates c-Jun NH2-terminal kinase in pancreatic b-cells."Diabetes. 52・11. 2720-2730 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Chen Y., et al.: "Rab27b is associated with fusiform vesicles and may be involved in targeting uroplakins to urothelial apical membranes."Proc.Natl.Acad.Sci., USA. 24. 14012-14017 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Izumi T., et al.: "Roles of Rab27 and its effectors in the regulated secretory pathways."Cell Struct.Funct.. 28・5. 465-474 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hosaka M., et al.: "Secretogranin III binds to cholesterol in the secretory granule membrane as an adapter for chromogranin A."J.Biol.Chem.. 279. 3627-3634 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Fujisawa T., et al.: "Functional localization of proprotein-convertase furin and its substrate TGFβ in EGF Receptor-expressing gastric chief cells."Growth Factors. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Torii S., et al.: "Rab27 effector granuphilin promotes the plasma membrane targeting of insulin granules via interaction with syntaxin 1a"J.Biol.Chem.. 279(in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yi Z, Yokota H, Torii S, Aoki T, Hosaka M, Zhao S, Takata K, Takeuchi T, Izumi T: "The Rab27a/granuphilin complex regulates the exocytosis of insulin-containing dense-core granules"Mol. Cell. Biol.. 22. 1858-1867 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Zhao S, Torii S, Yokota-Hashimoto H, Takeuchi T, Izumi T: "Involvement of Rab27b in the regulated secretion of pituitary hormones"Endocrinology. 143. 1817-1824 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nagashima K, Torii S, Yi Z, lgarashi M, Okamoto K, Takeuchi T, Izumi T: "Melanophilin directly links Rab27a and myosin Va through its distinct coiled-coil regions"FEBS Lett.. 517. 233-238 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Torii S, Zhao S, Yi Z, Takeuchi T, Izumi T: "Granuphilin modulates the exocytosis of secretory granules through interaction with syntaxin 1a"Mol. Cell. Biol.. 22. 5518-5526 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Izumi T, Yokota-Hashimoto H, Zhao S, Wang J, Halban PA, Takeuchi T: "Dominant negative pathogenesis by mutant proinsulin in the Akita diabetic mouse"Diabetes. 52. 409-416 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yaguchi M, Nagashima K, Izumi T, Okamoto K: "Neurological study of C57BL/6Akita mouse, type 2 diabetic model : enhanced expression of αB-crystallin in oligodendrocytes"Neuropathology. (in press). (2003)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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