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Generation of Wolfram syndrome mice, aiming at development of new therapeutics for diabetes through preserving pancreatic beta cells

Research Project

Project/Area Number 12357007
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Metabolomics
Research InstitutionTohoku University (2001-2002)
Yamaguchi University (2000)

Principal Investigator

OKA Yoshitomo  Tohoku University Graduate School of Medicine, Division of Molecular Metabolism and Diabetes, Professor, 大学院・医学系研究科, 教授 (70175256)

Co-Investigator(Kenkyū-buntansha) TAKAHASHI Kazuma  Tohoku University Hospital, Department of Diabetes and Metabolism, Research Associate, 医学部附属病院, 助手 (60292215)
HINOKIO Yoshinori  Tohoku University Hospital, Department of Diabetes and Metabolism, Research Associate, 医学部附属病院, 助手 (10282071)
KATAGIRI Hedeki  Tohoku University Graduate School of Medicine, Division of Advanced Therapeutics for Metabolism and Diabetes, Professor, 大学院・医学系研究科, 教授 (00344664)
ISHIHARA Hisamitsu  Tohoku University Hospital, Department of Diabetes and Metabolism, Research Associate, 医学部附属病院, 助手
HIRAI Masashi  Tohoku University Hospital, Department of Diabetes and Metabolism, Research Associate, 医学部附属病院, 助手 (80312578)
谷澤 幸生  山口大学, 医学部・附属病院, 講師 (00217142)
湯尻 俊昭  山口大学, 医学部, 日本学術振興会特別研究員(PD)
佐々木 輝昌  山口大学, 医学部・附属病院, 医員(臨床)
竹田 孔明  山口大学, 医学部・附属病院, 医員(臨床)
松本 健  田辺製薬, 創薬研究所・薬効評価ユニット, 副ユニット長(研究職)
Project Period (FY) 2000 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥40,700,000 (Direct Cost: ¥34,700,000、Indirect Cost: ¥6,000,000)
Fiscal Year 2002: ¥13,000,000 (Direct Cost: ¥10,000,000、Indirect Cost: ¥3,000,000)
Fiscal Year 2001: ¥13,000,000 (Direct Cost: ¥10,000,000、Indirect Cost: ¥3,000,000)
Fiscal Year 2000: ¥14,700,000 (Direct Cost: ¥14,700,000)
KeywordsDiabetes / Insulin / pancreatic β cell / Wolfram syndrome / WFS1 / endoplasmic reticulum / knock-out mice / アポトーシス / 小胞体ストレス / ER(endoplasmic reticulum) / インスリン分泌 / 視神経萎縮 / endoplasmic reticulum
Research Abstract

Wolfram syndrome is an autosomal recessive disorder associated with juvenile onset diabetes mellitus, optic atrophy, sensorineural deafness and diabetes insipidus. We identified, employing positional cloning, a gene responsible for this disorder and designated it WFS1. We also showed WFS1 protein to be localized in the ER membrane. In addition, WFS1 shares some sequence similarity with yeast Hrd3p, which is involved in ER-associated degradation of malfolded proteins. Thus, though WFS1 protein appears to play a role in the ER-stress response, its precise function remains to be clarified. To elucidate the functions of this novel protein and the pathophysiology of Wolfram syndrome, we have generated mice lacking the WFS1 gene (WFS1-KO). WFS1-KO mice are normal in appearance, growth and fertility Blood glucose levels in male WFS1-KO mice start to rise at around 12 weeks and are significantly higher than those of wild-type mice at 24 weeks (267±33 vs 146±34 mg/dl). This is associated with loss of islet β cells; whole pancreatic insulin content in WFS1-KO mice was 30-times lower than that in wild-type mice (11±4 vs 287±34 ng/mg pancreas). Immunohistochemical analysis of the pancreas using an anti-WFS1 protein antibody revealed that WFS1 protein is absent from exocrine tissue, but is strongly expressed in endocrine β cells. WFS1 protein is not expressed in glucagon-positive cells and the majority of somatostatin-, and pancreatic polypeptide-positive cells are devoid of WFS1 immunoreactivity. In WFS1-KO mice, β cell number fell with age, while a cells were somewhat increased and were scattered throughout the islet. These results strongly suggest WFS1 protein to play a critical role in survival and/or regeneration of β cells and progressive loss of islet β cells to be the major cause of diabetes in this disorder.

Report

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

    (30 results)

All Other

All Publications (30 results)

  • [Publications] Suzuki Y, Tsukuda K, Taniyama M, Atsumi Y, Matsuoka K, Oka Y: "Lipoma and sensory neuropathy in mitochondrial diabetes associated with tRNA mutation at position 3271"Diabates Care. 25. 407-408 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tanizawa Y, Nakai K, Sasaki T, Anno T, Ohta Y, Inoue H, Matsuo K, Koga M, Furukawa S, Oka Y: "Unregulated elevation of glutamate dehydrogenase activity induces glutamine-stimulated insulin secretion : Identification and characterization of a GLUDi gene mutation, and insulin secretion studies with MIN6 cells overexpressing the mutant GDH"Diabetes. 51. 712-717 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nakazaki M, Kakei M, Ishihara H, Koriyama N, Hashiguchi H, Aso K, Fukudome M, Oka Y, Yada T: "Association of upregulated activity of KATP channels with impaired insulin secretion in UCP1-expressing insulinoma cells"J Physiology. 540・3. 781-789 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yamasoba T, Goto Yu-ichi, Oka Y, Nishino I, Tsukuda K, Nonaka I: "Atypical muscle pathology and a survey of cis-mutations in deaf patients harboring a 1555 A-to G point mutation in the mitochondrial ribosomal RNA gene"Neuromuscular Disorders. 12. 506-512 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Suzuki Y, Suzuki S, Taniyama M, Muramatsu T, Ohta S, Oka Y, Atsumi Y, Matsuoka K: "Multiple cranial mononeuropathies with acetylcholine receptor antibody in mitochondrial diabetes"Diabetes Care. 26. 1318 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Cryns K, Thys S, Van Laer L, Oka Y, Pfister M, Van Nassauw L, Smith RJ, Timmermans J-P, Van Camp G: "The WFS1 gene, responsible for low frequency sensorineural hearing loss and Wolfram syndrome, is expressed in a variety of inner ear cells"Histochem Cell Biol. 119. 247-256 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Suzuki Y, Tsukuda K, Taniyama M, Atsumi Y, Matsuoka K, Oka Y: "Lipoma and sensory neuropathy in mitochondrial diabetes associated with tRNA mutation at position 3271."Diabetes Care 25. 407-408 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tanizawa Y, Nakai K, Sasaki T, Ohta Y, Inoue H, Matuo K, Koga M, Furukawa S, Oka Y: "Unregulated elevation of glutamate dehydrogenase activity induces glutamine-stimulated insulin secretion: Identification and characterization of a GLUD1 gene mutation, and insulin secretion studies with MIN6 cells overexpressing the mutant GDH."Diabetes 51. 712-717 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nakazaki M, Kakei M, Ishihara H, Koriyama N, Hashiguchi H, Aso K, Fukudome M, Oka Y, Yada T: "Association of upregulated activity of KATP channels with impaired insulin secretion in UCP1-expressing insulinoma cells."J Physiology 540. 781-789 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yamasoba T, Goto Yu-ichi, Oka Y, Nishino I, Tsukuda K, Nonaka I: "Atypical muscle pathology and a survey of cis-mutations in deaf patients harboring a 1555 A-to G point mutation in the mitochondrial ribosomal RNA gene."Neuromuscular Disorders 12. 506-512 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Suzuki Y, Suzuki S, Taniyama M, Muramatsu T, Ohta S, Oka Y, Atsumi Y, Matsuoka K: "Multiple cranial mononeuropathies with acetylcholine receptor antibody in mitochondrial diabetes."Diabetes Care 26. 1318 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Cryns K, Thys S, Van Laer L, Oka Y, Pfister M, Van Nassauw L, Smith RJ, Timmermans J-P, Van Camp G: "The WFS1 gene, responsible for low frequency sensorineural hearing loss and Wolfram syndrome, is expressed in a variety of inner ear cells."Histochem Cell Biol 119. 247-256 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Suzuki Y, Tsukuda K, Taniyama M, Atsumi Y, Matsuoka K, Oka Y: "Lipoma and sensory neuropathy in mitochondrial diabetes associated with tRNA mutation at position 3271"Diabetes Care. 25. 407-408 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tanizawa Y, Nakai K, Sasaki T, Anno T, Ohta Y, Inoue H, Matuo K, Koga M, Furukawa S, Oka Y: "Unregulated elevation of glutamate dehydrogenase activity induces glutamine-stimulated insulin secretion : Identification and characterization of a GLUD1 gene mutation, and insulin secretion studies with MIN6 cells overexpressing the mutant GDH"Diabetes. 51. 712-717 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nakazaki M, Kakei M, Ishihara H, Koriyama N, Hashiguchi H, Aso K, Fukudome M, Oka Y, Yada T: "Association of upregulated activity of KATP channels with impaired insulin secretion in UCP1-expressing insulinoma cells"J Physiology. 540・3. 781-789 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yamasoba T, Goto Yu-ichi, Oka Y, Nishino I, Tsukuda K, Nonaka I: "Atypical muscle pathology and a survey of cis-mutations in deaf patients harboring a 1555 A-to G point mutation in the mitochondrial ribosomal RNA gene"Neuromuscular Disorders. 12. 506-512 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Suzuki Y, Suzuki S, Taniyama M, Muramatsu T, Ohta S, Oka Y, Atsumi Y, Matsuoka K: "Multiple cranial mononeuropathies with acetylcholine receptor antibody in mitochondrial diabetes"Diabetes Care. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Cryns K, Thys S, Van Laer L, Oka Y, Pfister M, Van Nassauw L, Smith RJ, Timmermans J-P, Van Camp G: "The WFS1 gene, responsible for low frequency sensorineural hearing loss and Wolfram syndrome, is expressed in a variety of inner ear cells"Histochemistry and Cell Biology. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yamada T, et al.: "3-phosphoinostide-dependent protein kinase 1, an Akt1 kinase, is involved in dephosphorylation of Thr308 of Akt1 in Chinese hamster ovary cells"J Biol Chem. 276. 5339-5345 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Takeda K, et al.: "WFS1 (Wolfram syndrome 1) gene product : Predominant subcellular localization to endoplasmic reticulum in cultured cells and neuronal expression in rat brain"Hum Mol Genet. 10. 477-484 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Emoto M, et al.: "Troglitazone treatment increases plasma vascular endothelial growth factor in diabetic patients and its mRNA in 3T3-L1 adipocytes"Diabetes. 50. 1166-1170 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Okuya S, et al.: "Leptin increases the viability of isolated rat pancreatic islets by suppressing apoptosis"Endocrinology. 142. 4827-4830 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Suzuki Y, et al.: "Lipoma and sensory neuropathy in mitochondrial diabetes associated with tRNA mutation at position 3271"Diabetes Care. 25. 407-408 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tanizawa Y, et al.: "Unregulated elevation of glutamate dehydrogenase activity induces glutamine-stimulated insulin secretion : Identification and characterization of a GLUD1 gene mutation, and insulin secretion studies with MIN6 cells overexpressing the mutant GDH"Diabetes. (in press).

    • Related Report
      2001 Annual Research Report
  • [Publications] Tanizawa Y et al: "Genetic analysis of Japanese patients with persistent hyperinsulinemic hypoglycemia of infancy. Nucleotide-binding fold-2 mutation impairs cooperative binding of adenine nucleotides to sulfonylurea receptor 1."Diabetes. 49. 114-120 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yujiri T et al: "MEK kinase 1 gene disruption alters cell migration and c-Jun NH2-terminal kinas regulation but does not cause a measurable defectin NFkB activation."PNAS. 97. 7272-7 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Matsuo M et al: "Functional analysis of a mutant sulfonylurea receptor, SUR1-R1420C, that is responsible for persistent hyperinsulinemic hypoglycemia of infancy."J biol Chem. 275. 41184-91 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Takeda K et al: "WFS1(Wolfram syndrome 1) gene product : Predominant subcellular localization to endoplasmic reticulum in cultured cells and neuronal expression in rat brain."Hum Mol Genet. 10. 477-484 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] 井上寛: "医学のあゆみ「Wolfram症候群原因遺伝子(WFS1)の同定」"メディカルレビュー社. 6 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 竹田孔明: "Diabetes Frontier"メディカルレビュー社. 6 (2000)

    • Related Report
      2000 Annual Research Report

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

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