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2005 Fiscal Year Final Research Report Summary

Molecular Pathophysiology of Wolfram Syndrome and Endoplasmic Reticulum Stress-associated Pancreatic β-cell Failure.

Research Project

Project/Area Number 16390096
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Pathological medical chemistry
Research InstitutionYamaguchi University

Principal Investigator

TANIZAWA Yukio  Yamaguchi University, School of Midicine, Professor, 大学院・医学系研究科, 教授 (00217142)

Co-Investigator(Kenkyū-buntansha) MATSUBARA Atsushi  Yamaguchi University, Hospital, Assistant Professor, 医学部附属病院, 講師 (40311815)
YUJIRI Toshiaki  Yamaguchi University, Hospital, Assistant Professor, 医学部附属病院, 講師 (80346551)
UEDA Kohei  Yamaguchi University, Health Service Center, Assistant Professor, 保健管理センター, 講師 (50325221)
TURU Masatoshi  Yamaguchi University, Hospital, Research Associate, 医学部附属病院, 助手 (20379960)
TANABE Katsuya  Yamaguchi University, Hospital, Clinical Fellow, 医学部附属病院, 医員(臨床) (00397994)
Project Period (FY) 2004 – 2005
Keywordsdiabetes mellitus / endoplasmic reticulum stress / obesity / insulin secretion / Wolfram syndrome / β-cell
Research Abstract

Wolfram syndrome, caused by the mutations in the WFS1 gene, is characterized by juvenile onset diabetes mellitus and progressive optic atrophy. In the patient's islets, β-cells are selectively lost. The WFS1 gene encodes an endoplasmic reticulum (ER) membrane-embedded protein (Wolframin). We speculated that wolframin is involved in the ER stress responses. Treatment of MIN6 cells with ER stress-inducible chemical such as thapsigargin or tunicamycin, increased wfs1 mRNA levels. Human WFS1 promoter was activated by treatment of the cells with these reagents when it was examined by the WFS1 gene promoter-luciferase reporter system. In addition, we found increased WFS1 mRNA and protein expression in the mouse insulinoma cells derived from Akita mouse, in which ER stress is induced by the misfolded mutant insulin expression. WFS1 promoter was more active in these Akita mouse-derived β-cells. Collectively, our data suggest that WFS1 expression is induced by ER stress.
In Wfs1-/- mice, pancreatic β-cell loss largely depends on their genetic backgrounds. To test the hypothesis that the Wfs1-lacking pancreatic β-cells are more susceptible to ER stress, we crossed Wfs1-/- mice on the C57BL/6J background with agouti lethal yellow (A/Ay) mice, a genetic model of mild obesity/insulin resistance. ER chaperon Bip/GRP78 expression increased in the pancreatic islets of A/Ay mice, suggesting the presence of ER stress due to increased demands of insulin biosynthesis and secretion. Although neither the Wfs1-/- mice or the A/Ay mice on the C57BL/6J background develop overt diabetes, all Wfs1-/- A/Ay mice developed overt diabetes. Pancreatic β-cells markedly reduced in the Wfs1-/- A/Ay mice due to apoptosis. These data suggest that the pancreatic β-cells lacking Wfs1 to be more susceptible to ER stress-induced apoptosis.

  • Research Products

    (14 results)

All 2006 2005 2004

All Journal Article (13 results) Book (1 results)

  • [Journal Article] A novel mutation of WFS1 gene in a Japanese man of Wolfram syndrome with positive diabetes-related antibodies.2006

    • Author(s)
      Nakamura A et al.
    • Journal Title

      Diabetes Res Clin Pract (In press)

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Myosin motor Myolc and its receptor NEMO/IKK-g promote TNF-a induced serine^<307> phosphorylation of IRS-1.2006

    • Author(s)
      Nakamori Y et al.
    • Journal Title

      J Cell Biol. (In press)

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Estrogen receptor a regulates insulin sensitivity through IRS-1 tyrosine phosphorylation in mature 3T3-L1 adipocytes.2006

    • Author(s)
      Muraki K et al.
    • Journal Title

      Endocrine J (In press)

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] A novel mutation of WFS1 gene in a Japanese man of Wolfram syndrome with positive diabetes-related antibodies.2006

    • Author(s)
      Nakamura A
    • Journal Title

      Diabetes Res Clin Pract. (in press)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Myosin motor Myo1c and its receptor NEMO/IKK-g promote TNF-a induced serine307 phosphorylation of IRS-1.2006

    • Author(s)
      Nakamori Y
    • Journal Title

      J Cell Biol. (in press)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Estrogen receptor a regulates insulin sensitivity through IRS-1 tyrosine phosphorylation in mature 3T3-L1 adipocytes.2006

    • Author(s)
      Muraki K
    • Journal Title

      Endocrine J. (in press)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Endoplasmic Reticulum Stress induces Wfsi Gene Expression in Pancreatic β-cells via Transcriptional Activation.2005

    • Author(s)
      Ueda K et al.
    • Journal Title

      Eur j Endocrinol 153

      Pages: 167-176

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Severe Congenital Hyperinsulinism due to a Mutation in the Kir6.2 Subunit of the KATP Channel Impairing Trafficking and Function.2005

    • Author(s)
      Marthinet E et al.
    • Journal Title

      J Clin Endocrinol Metab 90

      Pages: 5401-5406

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Endoplasmic Reticulum Stress Induces Wfs1 Gene Expression Pancreatic β-cells via Transcriptional Activation.2005

    • Author(s)
      Ueda K
    • Journal Title

      Eur J Endocrinol 153

      Pages: 167-176

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Severe Congenital Hyperinsulinism due to a Mutation in the Kir6.2 Subunit of the KATP Channel Impairing Trafficking and Function.2005

    • Author(s)
      Marthinet E
    • Journal Title

      J Clin Endocrinol Metab. 90

      Pages: 5401-5406

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Wolfram Syndrome2005

    • Author(s)
      Tanizawa Y
    • Journal Title

      New Frontier of Diabetes

      Pages: 390

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Feeding induces expression of heat shock proteins that reduce oxidative stress.2004

    • Author(s)
      Katsuki K et al.
    • Journal Title

      FEBS Lett. 571

      Pages: 187-191

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Feeding induces expression of heat shock proteins that reduce oxidative stress.2004

    • Author(s)
      Katsuki K
    • Journal Title

      FEBS Lett. 571

      Pages: 187-191

    • Description
      「研究成果報告書概要(欧文)」より
  • [Book] 糖尿病の最新医療(先端医療シリーズ32)2005

    • Author(s)
      谷澤 幸生, 他
    • Total Pages
      390
    • Publisher
      先端医療技術研究所
    • Description
      「研究成果報告書概要(和文)」より

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Published: 2007-12-13  

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