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Elucidation of diabetes-related genes

Research Project

Project/Area Number 13204062
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionTohoku University

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) KATAGIRI Hideki  Tohoku University Graduate School of Medicine, Division of Advanced Therapeutics for Metabolic Diseases, Professor, 大学院医学系研究科, 教授 (00344664)
HINOKIO Yoshinori  Tohoku University Hospital, Division of Molecular Diabetes and Metabolism, Lecture, 病院・講師 (10282071)
ISHIHARA Hisamitsu  Tohoku University Hospital, Division of Molecular Diabetes and Metabolism, Research Associate, 病院・助手 (60361086)
平井 完史  東北大学, 病院・助手 (80312578)
谷澤 幸生  山口大学, 医学部・附属病院, 講師 (00217142)
Project Period (FY) 2001 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥33,500,000 (Direct Cost: ¥33,500,000)
Fiscal Year 2004: ¥7,500,000 (Direct Cost: ¥7,500,000)
Fiscal Year 2003: ¥8,000,000 (Direct Cost: ¥8,000,000)
Fiscal Year 2002: ¥8,000,000 (Direct Cost: ¥8,000,000)
Fiscal Year 2001: ¥10,000,000 (Direct Cost: ¥10,000,000)
KeywordsDiabetes / Insulin secretion / pancreatic B cell / Wolfram syndrome / Endoplasmic reticulum stress / cell cycle / SNP / ウェルナー症候群 / GPLD1 / GDH / GLUD1 / PPARa / glutamate
Research Abstract

Wolfram syndrome, an autosomal recessive disorder associated with diabetes mellitus and optic atrophy is caused by mutations in the WFS1 gene encoding an endoplasmic reticulum (ER) membrane protein. We herein report that pancreatic islets of wfs1-deficient mice exhibit increases in PKR-like ER kinase phosphorylation, chaperone gene expressions and active XBP1 protein levels, indicating an enhanced ER stress response. We established wfsl-deficient MIN6 clonal β-cells by crossing wfsl-deficient mice with mice expressing simian virus 40 large T antigen in β-cells. These cells show essentially the same alterations in ER stress responses as wfsl-deficient islets, which were reversed by re-expression of WFS1 protein or overexpression of GRP78, a master regulator of ER stress. In contrast, these changes are observed neither in heart, skeletal muscle, nor brown adipose tissues with WFS1-deficiency. The enhanced ER stress results in increased caspase 3 cleavage and reduced BrdU incorporation, indicating accelerated apoptotic processes and impaired cell cycle progression in the mutant islets. These changes are associated with increased expression of p21^<CIP1> in wfsl-deficient islets and clonal β-cells. Treatment of islets with thapsigargin, an ER stress inducer increased p21^<CIP1> expression, and forced expression of p21^<CIP1> reduced MIN6 β-cell numbers, suggesting that the ER stress-induced increase in p21^<CIP1> expression to be involved in β-cell loss in the mutant islets. These data indicate that WFS1-deficiency activates the ER stress response specifically in β-cells, causing β-cell loss through increased apoptosis and impaired cell cycle progression.

Report

(5 results)
  • 2005 Final Research Report Summary
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (27 results)

All 2006 2005 2004 Other

All Journal Article (10 results) Publications (17 results)

  • [Journal Article] Cell-type specific activation of metabolism reveals that β-cell secretion suppresses glucagon release from α-cells in rat pancreatic islets.2006

    • Author(s)
      Takahashi R, Ishihara H, Tamura A, et al.
    • Journal Title

      Am J Physiol Endocrinol Metab. 290

      Pages: 308-316

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] WRN gene 1367 Arg allele protects against development of type 2 diabetes mellitus2005

    • Author(s)
      Hirai M, Suzuki S, Hinokio Y, et al.
    • Journal Title

      Diabetes Res Clin Pract. 69

      Pages: 287-292

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Endoplasmic reticulum stress induces Wfs1 gene expression in pancreatic β-cells via transcriptional activation.2005

    • Author(s)
      Ueda K, Kawano J, Takeda 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
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Dissipating excess energy stored in the liver is a potential treatment strategy for diabetes associated with obesity.2005

    • Author(s)
      Ishigaki Y, Katagiri H, Yamada T, et al.
    • Journal Title

      Diabetes 54

      Pages: 322-332

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Constitutively active PDX1 induced efficient insulin production in adult murine liver.2005

    • Author(s)
      Imai J, Katagiri H, Yamada T, et al.
    • Journal Title

      Biochem Biophys Res Commun 326

      Pages: 402-409

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Genetic variants in the calpain-10 gene and the development of type 2 diabetes in the Japanese population.2005

    • Author(s)
      Iwasaki N, Horikawa Y, Tsuchiya T, et al.
    • Journal Title

      J Hum Genet. 50

      Pages: 92-98

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Disruption of the WFS1 gene in mice causes progressive beta-cell loss and impaired stimulus-secretion coupling in insulin secretion.2004

    • Author(s)
      Ishihara H, Takeda S, Tamura A, Takahashi R, Yamaguchi S, Takei D, Yamada T, Inoue H, Soga H, Katagiri H, Tanizawa Y, Oka Y.
    • Journal Title

      Hum Mol Genet. 13

      Pages: 1159-1170

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Genetic variations at urotensin II and urotensin II receptor genes and risk of type 2 diabetes mellitus in Japanese.2004

    • Author(s)
      Suzuki S, Zong Wenyi, Hirai M, Hinokio Y, Suzuki C, Yamada T, Yoshizumi S, Suzuki M, Tanizawa Y, Matsunami A, Oka Y.
    • Journal Title

      Peptides 25

      Pages: 1803-1808

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Endoplasmic reticulum stress and N-glycosylation. modulate expression of WFS1 protein.2004

    • Author(s)
      Yamaguchi S, Ishihara H, Tamura A, Yamada T, Takahashi R, Takei D, Katagiri H, Oka Y
    • Journal Title

      Biochem Biophys Res Commun 325

      Pages: 250-256

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Overexpression of constitutively activated glutamate dehydrogenase induces insulin secretion through enhanced glutamate oxidation.2004

    • Author(s)
      Anno T, Uehara S, Katagiri H, Ohta Y, Ueda K, Mizuguchi H, Moriyama Y, Oka Y, Tanizawa Y.
    • Journal Title

      Am J Physiol. 286

    • Related Report
      2004 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. 26. 1318 (2003)

    • Related Report
      2003 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"Histochem Cell Biol. 119. 247-256 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Wenyi Z, Suzuki S, Hirai H, Hinokio Y, Tanizawa Y, Matsutani M, Satoh J, Oka Y: "Role of urotensin II gene in the genetic susceptibility to type 2 diabetes mellitus in Japanese"Diabetologia. 46. 972-976 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Watanabe M, Inukai K, Katagiri H, Awata T, Oka Y, Katayama S: "Regulation of PPAR gamma transcriptional activity in 3T3-L1 adipocytes"Biochem Biophys Res Comm. 300. 429-436 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Suzuki S, Oka Y, Kadowaki T, Kanatsuka A, Kuzuya T, Kobayashi M, Sanke T, Seino Y, Nanjo K: "Clinical features of diabetes mellitus with the mitochondrial DNA 3243(A-G) mutation in Japanese : Maternal inheritance and mitochondria-related complications"Diabetes Red Clin Pract. 59. 207-217 (2003)

    • Related Report
      2003 Annual Research Report
  • [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] 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). (2002)

    • 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] Wenyi Z, Suzuki S, Hirai H, Hinokio Y, Tanizawa Y, Matsutani M, Satoh J, Oka Y: "Role of Urotensin II Gene in the Genetic Susceptibility to Type 2 Diabetes Mellitus in Japanese"Diabetologia. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yamada T, et al.: "3-phosphoinositide-dependent protein kinase 1, an Aktl kinase, is involved in dephosphorylation of Tbr308 ofAktl in Chinese hamster ovary cells"I Biol Chem. 276. 5339-5345 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Takeda K, et al.: "WES1 (Wolfram syndrome 1) gene product : Predominant subceilular localization to endoplasniic reticulum in cultured cells and neuronal expression in rat bran"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 diabeti poatients 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 T, et al.: "Lipoma and sensory neuropathy in niltochondrial diabetes associated with tRNA Mutation at position 3271"Deabetes Care. 25. 407-408 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tanizawa T, et al.: "Unregulated elevation of glutamate dehydrogenase activity induces glutamine-stimula ed insulin secretion : Identification and characterization of a GLUD1 gene mutation, and insulin secretion studies with MJN6 cells overexpressing the mutant GDH"Diabetes. (in press).

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2018-03-28  

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