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A novel classification of type 2 diabetes based on genome informatics

Research Project

Project/Area Number 14013038
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

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

Principal Investigator

YAMAGATA Kazuya  Osaka University Graduate School of Medicine, Department of Metabolic Medicine, Assistant Professor, 医学系研究科, 助手 (70324770)

Project Period (FY) 2002 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥23,000,000 (Direct Cost: ¥23,000,000)
Fiscal Year 2004: ¥7,500,000 (Direct Cost: ¥7,500,000)
Fiscal Year 2003: ¥7,500,000 (Direct Cost: ¥7,500,000)
Fiscal Year 2002: ¥8,000,000 (Direct Cost: ¥8,000,000)
Keywordsdiabetes mellitus / gene / SNP / insulin / impaired insulin secretion / insulin resistance / HNF / collectrin / インスリン分泌 / アディポネクチン / PGC-1
Research Abstract

Defective glucose-stimulated insulin secretion from pancreatic b-cells and insulin resistance in muscle, liver, and adipose tissue are the main cause of huperglycemia in type 2 diabetes. The purpose of the present study is to establish of a novel classification of type 2 diabetes as a polygenic disease, based on the genetic susceptibility to impaired insulin secretion or insulin resistance.
We have previously shown that genetic mutations in the hepatocyte nuclear factor (HNF)-4a and HNF-1a genes cause a form of type 2 diabetes characterized by impaired insulin secretion. T1301 mutation is a relatively uncommon genetic variation in the HNF-4a gene, which affects a conserved amino acid in the DNA binding domain. We examined the significance of the polymorphism in the development of type 2 diabetes by case-control study with 777 Japanese subjects. The frequency of the T1301 mutation was significantly higher in the group of type 2 diabetes compared with control group (p=0.015, odds ratio 4.3, 95% Cl 1.24-14.98). To clarify the contribution of HNF-4a in glucose-stimulated insulin secretion from pancreatic b-cells, we generated b-cell specific HNF-4a knockout mice by Cre-Lox P system. HNF-4a knockout mice exhibited glucose intolerance and an impaired insulin response after glucose load. Patch clamp experiments revealed that the current density was significantly increased in the knockout mice, indicating the dysfunction of KATP channel in the knockout mice. We also studied the target genes of HNF-1a in pancreatic b-cells to clarify the molecular mechanism of HNF-1a diabetes. We found that collectrin, a recently cloned kidney specific gene of unknown function, is a novel target of HNF-1a in pancreatic b-cells. Collectrin bound to SNARE complex and facilitated SNARE complex formation. Collectrin is a novel regulator of SNARE complex formation and controls insulin secretion.

Report

(4 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • Research Products

    (24 results)

All 2005 2004 2003 2002 Other

All Journal Article (12 results) Patent(Industrial Property Rights) (1 results) Publications (11 results)

  • [Journal Article] The HNF-1 target Collectrin controls insulin exocytosis by SNARE complex formation.2005

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

      Cell Metab. 2

      Pages: 373-384

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Functional characterization of the HNF4α isoform (HNF4α8) expressed in pancreatic β-cells.2005

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

      Biochem. Biophys. Res. Commun. 329

      Pages: 984-990

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The HNF-1 target Collectrin controls insulin exocytosis by SNARE complex formation.2005

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

      Cell Metab. 2

      Pages: 373-384

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Functional characterization of the HNF4α isoform (HNF4α8) expressed in pancreatic β-cells.2005

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

      BBRC 329

      Pages: 984-990

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Functional characterization of the HNF4α isoform (HNF4α8) expressed in pancreatic β-cells2005

    • Author(s)
      Ihara A, Yamagata K et al.
    • Journal Title

      BBRC (in press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] The ER chaperone 150 kDa Oxygen Regulated Protein (ORP150) improves insulin resistance in type 2 diabetes mellitus2005

    • Author(s)
      Ozawa K, Yamagata K et al.
    • Journal Title

      Diabetes (in press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Inhibitory effect of small heterodimer partner on hepatocyte nuclear factor 4 mediates bile acid-induced repression of human angiotensinogen gene.2004

    • Author(s)
      Shimamoto Y, Yamagata K et al.
    • Journal Title

      J.Biol.Chem. 279

      Pages: 7770-7776

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Overexpression of pituitary adenylate cyclase-activating polypeptide in islets inhibits hyperinsulinemia and islet hyperplasia in agouti yellow mice.2004

    • Author(s)
      Tomimoto S, Yamagata K et al.
    • Journal Title

      J.Pharmacol.Exp.Ther. 309

      Pages: 796-803

    • Related Report
      2004 Annual Research Report
  • [Journal Article] T130I mutation in HNF-4α gene is a loss-of-function mutation in hepatocytes and is associated with late-onset Type 2 diabetes mellitus in Japanese subjects.2003

    • Author(s)
      Zhu Q.et al.
    • Journal Title

      Diabetologia 46

      Pages: 567-573

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Small heterodimer partner, an orphan nuclear receptor, augments PPARγ transactivation.2002

    • Author(s)
      Nishizawa H. et al.
    • Journal Title

      J. Biol. Chem. 277

      Pages: 1586-1592

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Overexpression of dominant-negative mutant HNF-1α in pancreatic β-cells causes abnormal islet architecture with decreased expression of E-cadherin, reduced β-cell proliferation and diabetes.2002

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

      Diabetes 51

      Pages: 114-123

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Hepatocyte nuclear factor-1α modulates pancreatic β-cell growth by regulating the expression of insulin-like growth factor-1 in INS-1 cells.2002

    • Author(s)
      Yang Q.et al.
    • Journal Title

      Diabetes 51

      Pages: 1785-1792

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Patent(Industrial Property Rights)] 2型糖尿病および動脈硬化のマーカー、およびこれを検出するためのプローブならびにプライマー2003

    • Inventor(s)
      山縣和也
    • Industrial Property Number
      2003-079426
    • Filing Date
      2003-03-24
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Zhu Q, Yamagata K et al.: "T130I mutation in HNF-4α gene is a loss-of-function mutation in hepatocytes and is associated with late-onset Type 2 diabetes mellitus in Japanese subjects."Diabetologia. 46. 567-573 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yamamoto K, Yamagata K et al.: "Overexpressipn of PACAP in transgenic mouse pancreatic β cells enhances insulin secretion and ameliorates streptozotocin-induced diabetes."Diabetes. 52. 1155-1162 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yamagata K: "Regulation of pancreatic β-cell function by the HNF transcription network : Lessons from maturity-onset diabetes of the young (MODY)."Endocr J. 50. 491-499 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Li M, Yamagata K et al.: "Analysis of expression profiles of islet-associated transcription and growth factors during β-cell neogenesis from duct cells in partially duct-ligated mice."Pancreas. 27. 345-355 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Iwahashi H, Yamagata K et al.: "Plasma adiponectin levels in women with anorexia nervosa."Horm Metab Res. 35. 537-540 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shimamoto Y, Yamagata K et al.: "Inhibitory effect of small heterodimer partner on hepatocyte nuclear factor 4 mediates bile acid-induced repression of human angiotensinogen gene."J Blol Chem. (in press).

    • Related Report
      2003 Annual Research Report
  • [Publications] Issei Yoshiuchi et al.: "Identification of a gain-of-function mutation in the HNF-1β gene in a Japanese family with MODY"Diabetologia. 45. 153-154 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hiromi Iwahashi et al.: "Thyroid hormone receptor interacting protein 3 (Trip3) is a novel coactivator of hepatocyte nuclear factor-4α"Diabetes. 51. 910-914 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Qin Yang et al.: "Hepatocyte nuclear factor-1a modulates pancreatic β-cell growth by regulating the expression of insulin-like growth factor-1 in INS-1 cells"Diabetes. 51. 1785-1792 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takao Nammo et al.: "Expression profile of MODY3/HNF-1α protein in the developing mouse pancreas"Diabetologia. 45. 1142-1153 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Akihisa Imagawa et al.: "Elevated serum concentration of adipose-derived factor, adiponectin, in patients with type 1 diabetes"Diabetes Care. 25. 1665-1666 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2018-03-28  

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