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Establishment of detection tool for risk of type 2 diabetes using mice of 'digenic' form of type 2 diabetes

Research Project

Project/Area Number 13557091
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Metabolomics
Research InstitutionGUNMA UNIVERSITY

Principal Investigator

HORIKAWA Yukio  Gunma University, Inst.Mol.Cell.Reg., Associate Professor, 生体調節研究所, 助教授 (10323370)

Co-Investigator(Kenkyū-buntansha) TAKEDA Jun  Gunma University, Inst.Mol.Cell.Reg., Professor, 生体調節研究所, 教授 (40270855)
正 公枝  群馬大学, 生体調節研究所, 教務員 (40201561)
Project Period (FY) 2001 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥11,800,000 (Direct Cost: ¥11,800,000)
Fiscal Year 2003: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 2002: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2001: ¥5,300,000 (Direct Cost: ¥5,300,000)
Keywordstype 2 diabetes / calpain-10 / transgenic mice / knockout mice / カルパイン3 / 疾患感受性多型
Research Abstract

Multiple genetic and environmental factors cooperate to develop polygenic disease like type2 diabetes. The first identified susceptibility gene to type 2 diabetes, i.e.calpain 10, increases the risk of the disease in concert with the NIDDM3 gene located at chromosome 15. As the calpain 3 gene is located in the susceptibility gene locus NIDDM3, we planned to generate transgenic mice overexpressing either human calpain 10 or calpain 3 in pancreatic β cells and skeletal muscles. We first generated transgenic mice overexpressing calpain 10 either in pancreatic β cells or in skeletal muscles. We also generated conventional calpain 10 knock-out mice in collaboration with the University of Chicago. While calpain 3 knock-out mice had been generated by another group and were provided for us for phisiological analyses, we could not obtain any significant data that would relate calpain-3 with type 2 diabetes.
On the other hand, higher increase in body weight and insufficiency of early insulin secretion after glucose intake were observed with the transgenic mice of calpain 10 overexpression in pancreatic β cells. We performed real-time PCR using pancreatic islets isolated from these transgenic mice in order to examine the expression level of known MODY genes and diabetes related molecules, resulting in the identification of significant change of Glut2 which is involved in the HNF cascade. We also succeeded in generating calpain 10 knock-out mice and demonstrated that calpain 10 mediated ryanodine-induced apoptosis induced by the fatty acid palmitate and low glucose. Finally we generated transgenic mice overexpressing human calpastatin and found that inhibition of calpain activity in muscle is associated with increases in GLUT4 protein and muscle mass.

Report

(4 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (29 results)

All Other

All Publications (29 results)

  • [Publications] Horikawa Y. et al.: "Genetic variations in calpain-10 gene are not a major factor in the occurrence of type 2 diabetes in Japanese"J Clin Endocrinol Metab. 88. 244-247 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Zhou YP. et al.: "A 48-hour exposure of pancreatic islets to calpain inhibitors impairs mitochondrial fuel metabolism and the exocytosis of insulin"Metabolism. 52. 528-534 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Weedon MN. et al.: "Meta-analysis confirms a role for Calpain-10 variation in type 2 diabetes susceptibility"Am.J.Hum.Genet. 73. 1208-1212 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Otani K et al.: "Calpain system regulates muscle mass and glucose transporter GLUT4 turnover"J.Biol.Chem. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Johnson-JD et al.: "RyR2 and calpain-10 delineate a novel apoptosis pathway in pancreatic islets."J.Biol.Chem. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sreenan SK et al.: "Calpains play a role in insulin secretion and action."Diabetes. 50. 2013-2020 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Evans JC et al.: "Studies of association between the gene for calpain-10 and type 2 diabetes mellitus in the United Kingdom."Am J Hum Genet. 69. 544-552 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tonooka N et al.: "High frequency of mutations in the HNF-1a gene in non-obese patients with diabetes of youth in Japanese and identification of a case of digenic inheritance."Diabetologia. 45. 1709-1712 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Horikawa Y et al.: "Genetic variations in calpain-10 gene are not a major factor in the occurrence of type 2 diabetes in Japanese."J Clin Endocrinol Metab. 88. 244-247 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Zhu Q et al.: "T1301 mutation in HNF-4a gene is a loss-of-function mutation and is associated with late-onset type 2 diabetes in Japanese subjects"Diabetologia. 46. 567-573 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Horikawa Y et al.: "Identification of a novel variant of the Phosphoenolpyruvate Carboxykinase Gene Promoter in Japanese Patients with Type 2 Diabetes."Horm Metab Res. 35. 308-312 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Jin L et al.: "Expression profile of mRNAs from human pancreatic islet tumors."J Mol Endocrinol. 31. 519-528 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Weedon MN et al.: "Meta-analysis confirms a role for Calpain-10 variation in type 2 diabetes susceptibility."Am J Hum Genet. 73. 1208-1212 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] So WY et al.: "Genetic variants of hepatocyte nuclear factor-1beta in Chinese young-onset diabetic patients with nephropathy."J Diabetes Complications. 17. 369-373 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Johnson JD et al.: "RyR2 and calpain-10 delineate a novel apoptosis pathway inpancreatic islets."J Biol Chem. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Otani K et al.: "Calpain system regulates muscle mass and glucose transporter GLUT4 turnover."J Biol Chem. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Horikawa Y.et al.: "Genetic variations in calpain-10 gene are not a major factor in the occurrence of type 2 diabetes in Japanese"J Clin Endocrinol Metab. 88. 244-247 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Zhou YP.et al.: "A 48-hour exposure of pancreatic islets to calpain inhibitors impairs mitochondrial fuel metabolism and the exocytosis of insulin"Metabolism. 52. 528-534 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Weedon MN.et al.: "Meta-analysis confirms a role for Calpain-10 variation in type 2 diabetes susceptibility"Am.J.Hum.Genet. 73. 1208-1212 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Otani K et al.: "Calpain system regulates muscle mass and glucose transporter GLUT4 turnover"J.Biol.Chem. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Lynn, S. et al.: "Variation in the calpain-10 gene affects blood glucose levels in the British population"Diabetes. 51. 247-250 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Fullerton, S.M. et al.: "Geographic and haplotype structure of candidate type 2 diabetes susceptibility variants at the calpain-10 locus"Am. J. Hum. Genet.. 70. 1096-1106 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ehrmann, D.A. et al.: "Relationship of calpain-10 genotype to phenotypic features of polycystic ovary syndrome"J Clin Endocrinol Metab. 87. 1669-1673 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Shore, A.C.et al.: "Association of the calpain-10 gene with microvascular function"Diabetologia. 45. 899-904 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tonooka N. et al.: "High frequency of mutations in the HNF-1α gene in non-obese patients with diabetes of youth in Japanese and identification of a case of digenic inheritance"Diabetologia. 45. 1709-1712 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Del Bosque-Plata, L., et al.: "β-cell transcription factors and diabetes : no evidense for diabetes-associated mutations in the coding region of the proendocrine neurogenin 3 gene (NEUROG3) in Japanese patients with MODY"Diabetes. 50. 694-696 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yang, X., et al.: "Reduced skeletal muscle calpain-10 transcript level is due to a cumulative decrease in major isoforms"Mol.Genet.Metab. 73(1). 111-113 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Sreenan, S.K., et al.: "Calpains play a role in insulin secretion and action"Diabetes. 50. 2013-2020 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Evans, J.C., et al.: "Association studies of the calpain-10 gene with type 2 diabetes mellitus in the United Kingdom"Am, J.Hum.Genet. 69(3). 544-552 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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