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Identification of NIDDM susceptibility genes in the Japanese population by candidate gene approach and whole genome mapping.

Research Project

Project/Area Number 07457220
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field 内分泌・代謝学
Research InstitutionUniversity of Tokyo

Principal Investigator

KADOWAKI Takashi  University of Tokyo.Assistant, 医学部・附属病院・第三内科, 助手 (30185889)

Co-Investigator(Kenkyū-buntansha) MORI Yasumichi  University of Tokyo, medical staff, 医学部・附属病院・第三内科, 医員
ETO Kazuhiro  University of Tokyo, medical staff, 医学部・附属病院・第三内科, 医員
YASUDA Kazuki  University of Tokyo, medical staff, 医学部・附属病院・第三内科, 医員
Project Period (FY) 1995 – 1996
Project Status Completed (Fiscal Year 1996)
Budget Amount *help
¥6,700,000 (Direct Cost: ¥6,700,000)
Fiscal Year 1996: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1995: ¥5,300,000 (Direct Cost: ¥5,300,000)
KeywordsCommon NIDDM / sib pair analysis / whole genome mapping / candidate genes / beta3 adrenergic receptor / obesity / UCP / PPARgamma / polygenic disease / 候補遺伝子アプローチ / マイクロサテライトマーカー / NIDDM1 / NIDDM2 / NIDDM / 原因遺伝子 / 遺伝子マッピング
Research Abstract

1.Common NIDDM gene mapping.
We attempt to employ affected sib pair analysis for the identification of common NIDDM genes. We have collected DNA sample from 250 affected sib pairs of NIDDM from outpatients clinic of Tokyo Unibersity Hospital. We have also gathered the detailed clinical information such as family history, obesity, age of onset, insulin secretory capacity and treatment modality for all of the affected sib pairs. We plan to initiate whole genome mapping using microsatellite markers located every 10cM on the genome. We Iso started analysis of candidate Ioci revealed in the similar studies in other ethnic groups such as NIDDM1 and NIDDM2. We found that these loci are not the major Ioci for NIDDM susceptibility in the Japanese population.
2.Candidate gene approach
We studied several candidate genes for obesity, the most important risk factor for NIDDM in Japan. We identified several mutations in the genes for in the beta3 adrenergic receptor, UCP-1,3 and PPARgamma and are in the process of carrying out functional analysis and association studies. Among these, Trp64Arg mutation in the beta3 adrenergic receptor was found to be associated with higher BMI and increased visceral adiposity.

Report

(3 results)
  • 1996 Annual Research Report   Final Research Report Summary
  • 1995 Annual Research Report
  • Research Products

    (43 results)

All Other

All Publications (43 results)

  • [Publications] Yanagisawa,K.: "Mutation in the mitcchcndrial tRNA^<Leu> at position 3243 and sponanas abortions in Japanese women attending a clinic for diabetic pregnanies" Diabetologia. 38. 809-815 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Yasuda,K.: "No evidence for mutations in a putative subunit of the beta-cell ATP-sensitive potassium channel in Japanese NIDDM patients" Biochem.Biophys.Res.Commun.211. 1036-1040 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kadowaki,H.: "A mutation in the b3-adrenergic receptor gene is associated with obesity and hyperinsulinemia in Japanese Subjects." Biochem.Biophys.Res.Commun.210. 555-560 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Terauchi,Y.: "Pancreatic-Cell-Specitic targeted disruption of glucokinase gene." J.Biol.Chem.270. 30253-30256 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Aizawa,T.: "Analysis of poncreatic b cell in the mouse with targeted disneption of the pancreatic b cell-specitic glucokinase gene." Biochem.Biophys.Res.Commun.229. 460-465 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Terauchi,Y.: "Development of non-insulin-dependent diabetes mellifus in the double Knockout mice with disruption of insulin receptor substrate 1 and b-cell glucckinase genes : genetic reconstitution of diabetesas a polygenic disease" J.Clin.Invest.99. 861-866 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kim-Motoyama,H.: "Serum leptin levels are associated with hyperinsulinemia independent of body mass index but not with visceral obesity." Biochem.Biophys.Res.Commun.239. 340-344 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kim-Motoyama,H.: "A mutation of the b3-adrenargic receptor is associated with visceral obesity but decreased serum triglyceride." Diabetologia. 40. 469-472 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Takahashi,Y.: "A homozygous kinase-detective mutation in the insulin receptor gene in a patient with leprechaunism." Diabetologia. 40. 412-420 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Takahashi,Y.: "Two aberrant splicings caused by mutations in the insulin receptor gene in cultured lymphocytes from a patient with Rabson-Menden hall's syndrome." J.Clin.Invest.101. 588-594 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Yanagisawa, K.: "Mutation in the mitochondrial tRNA^<Leu> at position 3243 and spontaneous abortions in Japanese women attending a clinic for diabetic pregnancies." Diabetologia. 38. 809-815 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Yasuda, K.: "No evidence for mutations in a putative subnit of the beta-cell ATP-sensitive potassium channel in Japanese NIDDM patients." Biochem.Biophys.Res.Commun.211. 1036-1040 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kadowaki, H.: "A mutation in the b3-adrenergic receptor gene is associated with obesity and hyperinsulinemia in Japanese subjects." Biochem.Biophys.Res.Commun.210. 555-560 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Terauchi, Y.: "Pancreatic-Cell-specific targeted disruption of glucokinase gene." J.Biol.Chem.270. 30253-30256 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Aizawa, T.: "Analysis of pancreatic b cell in the mouse with targeted disruption of the pancreatic b cell-specific glucokinase gene." Biochem.Biophys.Res.Commun.229. 460-465 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Terauchi, Y.: "Development of non-insulin-dependent diabetes mellitus in the double knockout mice with disruption of insulin receptor substrate-1 and b-cell glucokinase genes : genetic reconstitution of diabetes as a polygenic disease." J.Clin.Invest.99. 861-866 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kim-Motoyama, H.: "Serum leptin levels are associated with hyperinsulinemia independent of body mass index but not with visceral obesity." Biochem.Biophys.Res.Commun.239. 340-344 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kim-Motoyama, H.: "A mutation of the b3-adrenergic receptor is associated with visceral obesity but decreased serum triglyceride." Diabetologia. 40. 469-472 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Takahashi, Y.: "A homozygous kinase-defective mutation in the insulin receptor gene in a patient with leprechaunism." Diabetologia. 40. 412-420 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Takahashi, Y.: "Two aberrant splicings caused by mutations in the insulin receptor gene in cultured lymphocytes from a patient with Rabson-Mendenhall's syndrome." J.Clin.Invest.101. 588-594 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Yamauchi,T.: "Insulin signaling and insulin actions in the muscle and liver of insulin resistant IRS-1 deficient mice." Mol.Cell.Biol.16. 3074-3084 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Tanaka,T.: "The extracellular signal-regulated kinase pathway phosphorylates AML1,an acute myeloid leukemia gene product,and potentially regulates its transactivation ability." Mol.Cell.Biol.16. 3967-3979 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Tobe,K.: "Csle enhances insulin-Stimulated dephos phorylation of focal adhesion proteins." Mol.Cell.Biol.16. 4765-4772 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Yamamoto-Honda,R.: "Mutant insulin receptor Substrate-1 unable to activate PI3 kinase faild to mediate insulin-Stimulated maturation of xenopus bevis oocytes." J.Biol.Chem.271. 28677-28681 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Biener,Y.: "Annexin II is a novel player in insulin signal transduction." J.Biol.Chem.271. 29489-29496 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Seko,Y.: "Hypoxia and Hypoxia/Reoxygenation Activate Paf-1,Mitogen-Activated protein kinase,Mitogen-Activated Protein Kinases,and S6 kinase in Cultured Rat Candiac Myocytes." Circ.Res.78. 82-90 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Kadowaki,T.: "Mechanism of Insulin Action" Asia Medical Journal. 39. 224-226 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Yamauchi,T.: "Anti-IRS-1 monoclonal antibody,6G5,cross-reacts to IRS-2." Hybridoma. 15. 307-309 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Kadowaki,T.: "Insulin resistance and growth retardation in mice lacking insulin receptor subtrate-1 and identification of insulin receptor sub trate-2." Diab.Med.13. 103-108 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Kadowaki,T.: "Signal transduction mechanism of insulin and insulin-like growth factor-1." Endocrine.J.43. 33-41 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Kadowaki,T.: "A new subtype of diabetes mellitus." A fundamental and clinical text. 591-595 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Suzuki,H.: "Diabetes mellitus with mitochondrial tRNALeu(UUR)mutation at position 3243:Characteristic Neuroimaging." Diabetes Care. 19. 739-743 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Yamamoto-Honda, R.: "Upstream mechanisms of glycogen synthase activation by insulin and insulin-like growth factor-I." J. Biol. Chem.270. 2729-2374 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Tobe, K.: "Identificaton of a 190-kDa protein as a novel substrate for the insulin receptor kinase functionally similar to insulin receptor substrote-1" J. Biol. Chem.270. 5698-5701 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Yanagisawa, K.: "Mutation in the mitochondrial +RNA leu at position 3243 and spontaneous abortions in Japanese women attending a clinic for diabetic pregnancies." Diabetologia. 38. 809-815 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Suzuki, Y.: "A case of diabetic amyotrophy associated with 3243 mitochondrial TRNALeu(UUR) mutation and successful therapy with Coenzyme Q_<10>" Endocrine J.42. 141-145 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Kadowaki, T.: "A subtype of diabetes mellitus associated with a mutation in the mitochondrial gene." Muscle ad Nerve. 3. 137-141 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Yamazaki, T.: "Mechanical Stress Activates Protein Kinase cascade of phosphonylation in neonatal rat cardiac myocytes." J. Clin. Invest.96. 438-446 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Yasuda, K.: "No evidence for mutations in a putative subunit of the beta-cell ATP-sensitive potassium channel in Japanese NIDDM patients." Biochem. Biophys. Res. Commun.211. 1036-1040 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Kaburagi, Y.: "The role of the NPXY motif in the insulin receptor in tyrosine phosphorylation of insulin receptor substrate-1 and Shc." Endocrinol.136. 3437-3443 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Kadowaki, H.: "A mutation in the β3-adrenergic receptor gene is associated with obesity and hyperinsulinemia in Japanese subjects." Biochem. Biophys. Res. Commun.210. 555-560 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Suzuki, Y.: "Diabetes mellitus with mitochondrial +RNALeu(UUR) mutation at position 3243" Diabetes Care. (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Terauchi, Y.: "Pancreatic-Cell-Specific Targeted Disruption of Glucokinase Gene." J. Biol. Chem. 270. 30253-30256 (1995)

    • Related Report
      1995 Annual Research Report

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Published: 1995-04-01   Modified: 2016-04-21  

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