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Generation and analysis of GIP Receptor deficient mice

Research Project

Project/Area Number 09671084
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field 内分泌・代謝学
Research InstitutionChiba University

Principal Investigator

YANO hideki  Chiba University Graduate school of Medicine, Associate Professor, 大学院・医学研究科, 助教授 (30288576)

Co-Investigator(Kenkyū-buntansha) JOMORI Takahito  Sanwakagaku Kenkyusho co., LTD, 創薬研究部, 課長
YUICHIRO Yamada  Kyoto University Graduate school of Medicine, Department of Metabolism and Clinical Nutrition, Associate Professor, 大学院・医学研究科, 助教授 (60283610)
SEINO Susumu  Chiba University Graduate school of Medicine, Department of Molecular Medicine, Professor, 大学院・医学研究科, 教授 (80236067)
Project Period (FY) 1997 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 1999: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1998: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1997: ¥1,700,000 (Direct Cost: ¥1,700,000)
KeywordsGIP receptor deficient mice / GIP modulation / Insulin secretion / Insulin resistance / High fat diet / Diabetes mellitus / ノックアウトマウス / GIP受容体 / ジーンターゲティング
Research Abstract

Gastric inhibitory polypeptide (GIP) acts as incretin, which promotes insulin secretion from pancreatic β-cells after meal ingestion. It has been shown that the insulinotropic effect of GIP is selectively impaired despite exaggerated GIP secretion in type 2 diabetic patients, suggesting that GIP modulaton of pancreatic β-cells is involved in the pathogenesis of type 2 diabetic mellitus. To analyze the role of GIP as a mediator of singals from the gut to the pancreatic β-cells, we have generated mice with a targeted disruption of the GIP receptor gene (GIPR). GIP stimulated insulin secretion 2.9-fold from the islets of GIPR+/+ mice, while GIP had no insulinotropic effect in GIPR-/- mice, indicating the absence of the GIP receptors in GIPR -/- mice. No significant differences in fasting glucose level and body weight were observed in GIPR-deficient mice. In IPGTT, blood glucose levels were not significantly different between GIPR -/- mice and GIPR +/+ mice. In contrast, GIPR-/- mice showed higher blood gulcose levels accompanied with impaired initial insulin response after oral glucse loading. The high fat diet did not alter blood glucose levels by compensatory higher insulin secretion after meal ingestion in GIPR +/+ mice, but further increased blood glucose levels without enhancement of insulin secretion in GIPR -/- mice. This demonstrates that insulin secretion, especially in the early phase after oral glucose loading, is mediated by GIP, and that GIP plays an important role in the compensatory enhancement of insulin secretion produced by a higher insulin demand. These results indicate that GIP may have critical role in vivo in the development of type 2 diabetes mellitus.

Report

(4 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • 1997 Annual Research Report
  • Research Products

    (15 results)

All Other

All Publications (15 results)

  • [Publications] N. Mitsuhashi et al.: "MTABC3, a novel mitochondrial ABC protein involved in iron homeostasis"J. Biol. Chem.. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] K. Miyawaki et al.: "Glucose Intolerance due to a defect in the entero-insular axis : a study in GIP-receptor knock-out mice"Proc Natl Acad Sci USA. 96. 14843-14847 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] J. Kawaki et al.: "Unresponsiveness to glibenclamide during chronic treatment induced by reduction of ATP-sensitive K^+ channel activity"Diabetes. 48. 2001-2006 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] M. Nishimura et al.: "Angiopoietin-3, a novel member of angiopoietin family"FEBS Lett. 448. 254-256 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] S. Seino, et al.: "The K_<ATP> Channel and Sulfonylurea Receptor in Molecular Basis of Endocrine Pancreas Development and Function (ed. by Hussain, M. A., Miller, C, P., et al.)"Kluwer Academic Publishers (in Press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] N. Mitsuhashi, et al.: "MTABC3, a novel mitochondrial ABC protein involved in iron homeostasis."J.Biol.Chem.. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] K. Miyawaki, et al.: "Glucose Intolerance due to a defect in the entero-insular axis : a study in GIP-receptor knock-out mice."Proc Natl Acad Sci USA. 96. 14843-14847 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] J. Kawaki. Et al.: "Unresponsiveness to glibenclamide during chronic treatment induced by reduction of ATP-sensitive KィイD1+ィエD1 channel activity"Diabetes. 48. 2001-2006 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] M. Nishimura, et al.: "Angiopoietin-3, a novel member of angiopoietin family."FEBS Lett. 448. 254-256 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] S. Seino, et al.: "In Molecular Basis of Endocrine Pnacreas Development and Function al., Hussain, M. A., and Habener J. F.(eds.) Kluwer Academic Publishers."The KィイD2ATPィエD2 Channel and Sulfonylurea Receptor. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] K. Miyawaki. et al.: "Glucose Intolerance due to a defect in the entero-insular axis : a study in GIP-receptor knock- out mice"Proc. Natl. Acad. Sci. USA. 96. 14843-14847 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Nishimura,M.et al.: "Angiopoientin-3,a novel member of the angiopoietin family." FEBS lett.(in press). (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Seino,S et al.: "The K_<ATP> Channel and Sulfonylurea Receptor.In Molecular Basis of Endocrine Pancreas Development and Function" Kluwer Academic Publishers(in press), (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Furuta, M.et al.: "Defective prohormone processing and altered pancreatic islet morphology in mice lacking active SPC2." Proc Natl Acad Sci USA. 94. 6646-6651 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Chien, E.K.et al.: "Increase in serum leptin receptor messenger RNA levels during pergnancy in rats." Biochem.Biophys.Res.Commun. 237. 476-480 (1997)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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