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Investigation For Molecular Mechanism Of Insulin Resistance In Transgenic Mice Expressing A Mutant Shp2

Research Project

Project/Area Number 10671062
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Metabolomics
Research InstitutionShiga University Of Medical Science

Principal Investigator

MAEGAWA Hiroshi  Shiga University Of Medical Science, Faculty Of Medicine, Rasearch Associates, 医学部, 助手 (00209363)

Project Period (FY) 1998 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2000: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1999: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1998: ¥1,600,000 (Direct Cost: ¥1,600,000)
KeywordsProtein-Tyrosine Phosphatase / SHP-2 / Transgenic Mice / Insulin Resistance / Protein phosphatase
Research Abstract

To elucidate roles of SHP-2, we generated transgenic (Tg) mice expressing a dominant negative mutant lacking PTPase domain (DPTP). On examining 2 lines of Tg mice identified by Southern blot, the transgene product was expressed in skeletal muscle liver and adipose tissues and insulin-induced association of insulin receptor substrate (IRS) 1 with endogenous SHP-2 was inhibited, confirming that DPTP has a dominant negative property. The intraperitoneal glucose loading test demonstrated an increase in blood glucose levels in Tg mice. Plasma insulin levels in Tg mice after 4 h fasting were 3 times greater with comparable blood glucose levels. To estimate insulin sensitivity by a constant glucose, insulin and somatostatin infusion, steady state blood glucose levels were higher, suggesting the presence of insulin resistance. Furthermore we observed the impairment of insulin-stimulated glucose uptake in muscle and adipocytes in the presence of physiological concentrations of insulin. Moreover, tyrosine-phosphorylation of IRS-1 and stimulation of phosphatidylinositol 3-kinase and Akt kinase activities by insulin were attenuated in muscle and liver. These results indicate that the inhibition of endogenous SHP-2 function by the overexpression of a dominant negative mutant may lead to impaired insulin sensitivity of glucose metabolism and thus SHP-2 may function to modulate insulin signaling in target tissues and these Tg mice are a unique model to investigate molecular mechanism for insulin resistance.

Report

(4 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • Research Products

    (22 results)

All Other

All Publications (22 results)

  • [Publications] Obata T,Maegawa H, et al: "High-glucose-induced abnormal Epidermal growth factor signaling"J.Biochem, Tokyo. 123. 813-820 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Fujita T,Maegawa H, et al: "Opposite Regulation of Tyrosine-phosphorylation of p130^<Cas> by Insulin and Insulin-like Growth Factor I"J.Biochem, Tokyo. 123. 1111-1116 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Maegawa H et al.: "A New Antidiabetic Agent(JTT-501) Acutely Stimulates Glucose Disposal Rates by Enhancing Insulin Signal Transduction in Skeletal Muscle"Diabetologia. 42. 151-159 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Maegawa H, et al: "The 3'-untranslated region polymorphism of the gene for skeletal muscle-specific glycogen-targeting subunit of protein phosphatase 1 in Japanese Type 2 diabetes mellitus"Diabetes. 48. 1469-1472 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Maegawa H, et al: "Expression of a dominant negative SHP-2 in transgenic mice induces insulin resistance."J.Biol.Chem.. 274. 30236-30243 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Egawa K,Maegawa H, et al.: "Protein Tyrosine Phosphatase-1B Negatively Regulates Insulin Signaling in L6 Myocytes and Fao Hepatoma Cells."J.Biol.Chem.. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Obata T, Maegawa H, Kashiwagi A: "Pillay TS and Kikkawa R.High-glucose-induced abnormal i Epidermal growth factor signaling."J.Biochem.Tokyo.. 123. 813-820 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Fujita T,Maegawa Kashiwagi A, Hirai H and Kikkawa R.: "Opposite regulation of tyrosine-phosphorylation of p130^<cas> by insulin and insulin-like growth factor I."J.Biochem.Tokyo.. 123. 1111-1116 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Maegawa H, Obata T, Shibata T, Fujita T, Ugi S, Morino K, Nishio Y, Kojima H, Hidaka H, Haneda M, Yasuda H, Kikkawa R and Kashiwagi A.: "A new antidiabetic agent (JTT-501) acutely stimulates glucose disposal rates by enhancing insulin signal transduction in skeletal muscle."Diabetologia. 42. 151-159 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Maegawa H, Shi K, Hidaka H, Iwai N, Nishio Y, Egawa K, Kojima H, Haneda M, Yasuda H, Nakamura Y, Kinoshita M, Kikkawa R and Kashiwagi A.: "The 3'-untranslated region polymorphism of the gene for skeletal muscle-specific glycogen-targeting subunit of protein phosphatase 1 in Japanese Type 2 diabetes mellitus."Diabetes. 48. 1469-1472 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Maegawa H, Hasegawa M, Sugai S, Ugi S, Obata T, Morino K, Egawa K, Fujita T, Sakamoto T, Nishio Y, Kojima H, Haneda M, Yasuda H, Kikkawa R and Kashiwagi A.: "Expression of a dominant negative SHP-2 in transgenic mice induces insulin resistance."J.Biol.Chem.. 274. 30236-43 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Egawa K, Nagashima N, Shrma PM, Maegawa H, Nagai Y, Kashiwagi A, Kikkawa R, and Olefsky JM.: "Persistent activation of phosphatidlylinositol 3-kinase cause insulin resistance due to accelerated insulin-induced IRS-1 degradation in 3T3-L1 adipocytes."Endocrinology. 141. 1930-1935 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Obata T, Yaffe MB, Leparc GG, Piro ET,Maegawa H, Kashiwagi A,Kikkawa R, and Cantley LC.: "Use of peptide and protein library screening to define optimal substrate motifs for AKT/PKB"J.Biol.Chem.. 275. 36108-36115 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Egawa K, Maegawa H, Shimizu S, Morino K, Nishio Y, Bryer-Ash, M, Cheung AT, Kolls JK, Kikkawa R and Kashiwagi A.: "Protein Tyrosine Phosphatase-1B Negatively Regulates Insulin Signaling in L6 Myocytes and Fao Hepatoma Cells."J.Biol.Chem.. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Egawa K,Nagashima N,Shrma PM,Maegawa H, et al.: "Persistent activation of phosphatidlylinositol 3-kinase cause insulin resistance due to accelerated insulin-induced IRS-1 degradation in 3T3-L1 adipocytes."Endocrinology. 141. 1930-1935 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Egawa K,Maegawa H, et al.: "Protein Tyrosine Phosphatase-1B Negatively Regulates Insulin Signaling in L6 Myocytes and Fao Hepatoma Cells."J.Biol.Chem.. (in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] Morino K,Maegawa H, et al.: "Insulin-induced JNK activation is negatively regulated by protein kinase C δ"Endocrinology. (in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] Maegawa H, et al: "The 3'-untranslated region polymorphism of the gene for skeletal muscle-specific glycogen-targeting subunit of protein phosphatase 1 in Japanese Type 2 diabetes mellitus"Diabetes. 48. 1469-1472 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Maegawa H, et al: "Expression of a dominant negative SHP-2 in transgenic mice induces insulin resistance"J. Biol. Chem.. 274. 30236-30243 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Obata T,Maegawa H,et al: "High-glucose-induced abnormal Epidermal growth factor signaling." J.Biochem,Tokyo. 123. 813-820 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Fujita T,Maegawa H,et al: "Opposite Regulation of Tyrosine-phosphorylation of p130^<Cas> by Insulin and Insulin-like Growth Factor I." J.Biochem,Tokyo. 123. 1111-1116 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Maegawa H,et al: "A New Antidiabetic Agent(JTT-501)Acutely Stimulates Glucose Disposal Rates by Enhancing Insulin Signal Transduction in Skeletal Muscle" Diabetologia. 42. 151-159 (1999)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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