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Molecular Pathogenesis of diabetes in rodent models

Research Project

Project/Area Number 12480249
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Laboratory animal science
Research InstitutionInstitute for Molecular and Cellular Regulation, Gunma University

Principal Investigator

IZUMI Tetsuro  Gunma University, Department of Molecular Medicine, Institute forMolecular and Cellular Regulation, Professor,, 生体調節研究所, 教授 (00212952)

Co-Investigator(Kenkyū-buntansha) 為本 浩至  自治医科大学, 大宮医療センター, 講師 (90292630)
Project Period (FY) 2000 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥12,000,000 (Direct Cost: ¥12,000,000)
Fiscal Year 2002: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2001: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2000: ¥5,600,000 (Direct Cost: ¥5,600,000)
Keywordsdiabetes / rodent models / quantitative trait locus / insulin secretion / pancreatic beta cells / 肥満
Research Abstract

We have investigated the molecular pathogenesis of diabetes using rodent disease models.
(1) TSOD mouse
We previously performed genetic analysis of diabetes and obesity in TSOD mice and identified three quantitative trait loci (QTLs). Our final goal is to identify genetic alterations at each QTL. For this-purpose, we have generated several congenic strains. For example, 17 congenic strains were constructed for the QTL on chromosome 2 that influences the body weight and plasma insulin levels of TSOD mice. By comparing phenotypes between the congenic strains and parental TSOD mice, the QTL regions can be narrowed down. In case of the QTL on chromosome 2, we can successfully define it to a 12.8-Mb region that contains 49 candidate genes.
(2) Akita mouse
We previously discovered that autosomal dominant diabetes in the Akita mouse is caused by mutation of, the insulin 2 gene, whose product replaces a cysteine residue that is engaged in the formation of an intramolecular disulfide bond. The heterozygous mice exhibit severe insulin deficiency despite coexpression of normal insulin molecules derived from three other wild-type alleles of the insulin 1 and 2 genes. We investigated the dominant-negative pathogenic mechanisms induced by the mutant proinsulin 2, and found that the trafficking of constitutively secreted alkaline phosphatase is significantly decreased in the islets of Akita mice. Morphologic analysis also revealed that secretory pathway organelle architecture is progressively devastated in the β-cells of Akita mice. These findings suggest that the organelle dysfunction due to the intracellular accumulation of misfolded proinsulin 2 is primarily responsible for the defect of coexisting wild-type insulin secretion in Akita β-cells.

Report

(4 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (25 results)

All Other

All Publications (25 results)

  • [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)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nagashima K, Torii S, Yi Z, Igarashi 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)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [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 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yaguchi M, Nagashima K, Izumi T, Okamoto K: "Neurological study of C57BL/6Akita mouse, type 2 diabetic model : enhanced expression of a B-crystallin oligodendrocytes"Neuropathology. (in press). (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yi Z, Yokota H, Torii S, Aoki T, Hosaka M, Zhao S, Takata K, Takeuchi T, and Izumi T.: "The Rab27a/granuphilin complex regulates the exocytosis of insulin-containing dense-core granules"Mol. Cell. Biol.. 22. 1858-1867 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Zhao S, Torii S, Yokota-Hashimoto H, Takeuchi T, and Izumi T: "Involvement of Rab27b in the regulated secretion of pituitary hormones"Endocrinology. 143. 1817-1824 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nagashima K, Torii S, Yi Z, Igarashi M, Okamoto K, Takeuchi T, and Izumi T: "Melanophilin directly links Rab27a and myosin Va through its distinct coiled-coil regions"FEBS Lett.. 517. 233-238 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Torii S, Zhao S, Yi Z, Takeuchi T, and Izumi T: "Granuphilin modulates the exocytosis of secretory granules through interaction with syntaxin la"Mol. Cell. Biol.. 22. 5518-5526 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Izumi T, Yokota-Hashimoto H, Zhao S, Wang J, Halban PA, and Takeuchi T: "Dominant negative pathogenesis by mutant proinsulin in the Akita diabetic mouse"Diabetes. 52. 409-416 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yaguchi M, Nagashima K, Izumi T, and Okamoto K: "Neurological study of C57BL/6Akita mouse, type 2 diabetic model : enhanced expression of αB-crystallin in oligodendrocytes"Neuropathology. in press..

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [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, Igarashi 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 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yaguchi M, Nagashima K, Izumi T, Okamoto K: "Neurological study of C57BL/6Akita mouse, type2 diabetic model : enhanced expression of a B-crystallin in oligodendrocytes"Neuropathology. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Negishi M., Lu D., Zhang Y., et al.: "Up-regulatory expression of furin and transforming growth factor β by fluid shear stress in vascular endothelial cells"Arterioscler. Thromb. Vasc. Biol.. 21. 785-790 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Sawada Y., Zhang B., Okajima F., et al.: "PTHrP increases pancreatic β-cell-specific function in well-differentiated cells"Mol. Cell. Endocrinol.. 182. 265-275 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yi Z., Yokota H., Torii S., et al.: "The Rab27A/granuphilin complex regulates the exocytosis of insulin-containing dense-core granules"Mol. Cell. Biol.. 22. 1858-1867 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Zhao S., Torii S., Yokota-Hashimoto H., et al.: "Involvement of Rab27b in the regulated secretion of pituitary hormones"Endocrinology. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Y.Sawada,T.Kameya, et al.: "Proprotein-processing endoprotease furin and its substrate parathyroid hormone-related protein are coexpressed specifically in insulinoma cells."Endocrine Pathology. 11. 31-39 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] M.Negishi,D.Lu, et al.: "Fluid shear stress induces co-expression of the proprotein-processing endoprotease furin and its substr ate transforming growth factor β (TGF β) in bovine aortic endothelial cells and furin is involved in the processing of TGF β precursor."Arteriosclerosis, Thrombosis, and Vascular Biology. (in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Y.Sawada,B.Zhang, et al.: "PTHrP increases pancreatic β-cell-specific function in well-differentiated cells."Mol.Cell Endocrinol.. (in press). (2001)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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