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The lack of caveolin-3, muscle-specific subtype of caveolin, leeds to the development of insulin resistance

Research Project

Project/Area Number 15590951
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Metabolomics
Research InstitutionYokohama City University

Principal Investigator

TOYA Yoshiyuki  Yokohama City University, Hospital, Assistant Professor, 医学部附属病院, 助教授 (30237143)

Co-Investigator(Kenkyū-buntansha) ISHIKAWA Yoshihiro  Yokohama City University, School of Medicine, Professor, 大学院・医学研究科, 教授 (40305470)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2004: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2003: ¥2,200,000 (Direct Cost: ¥2,200,000)
Keywordsinsulin resistance / insulin signal / caveolin / skeletal muscle / glycogen / type 2 diabetes / knockout mouse / gene transfer / インスリン
Research Abstract

Type 2 diabetes is preceded by the development of insulin resistance, in which the action of insulin is impaired, largely in skeletal muscles. Caveolin-3 is a muscle-specific subtype of caveolin, which is a major component of an example of a scaffolding protein, found within cellular membranes. In this study, we found that the lack of caveolin-3 led to the development of insulin resistance, as exemplified by decrease glucose uptake in skeletal muscles, impaired glucose tolerance test performance, and increases in serum lipids. Such impairments were markedly augmented in the presence of streptozotocin, a pancreatic β cell toxin, suggesting that the mice were susceptible to severe diabetes in the presence of an additional risk factor. Insulin-stimulated activation of receptors and downstream molecules, such as IRS-1 and Akt, was attenuated in the skeletal muscles of caveolin-3 null mice, but not in the liver, without affecting protein expression or sub cellular localization. Genetic tran … More sfer of caveolin-3 by needle injection restored insulin signaling in skeletal muscles. Our findings suggest that caveolin-3 is an enhancer of insulin signaling in skeletal muscles but does not act as a scaffolding molecule for insulin receptors. Moreover, We examined the effect of overexpressing caveolin-3 in the liver, which expresses little endogenous caveolin, by adenovirus-mediated gene transfer in diabetic animal models. Gene transfer significantly improved insulin sensitivity in vivo, as shown by an enhanced decline in blood glucose levels upon insulin injection, and thus improved glucose metabolism in diabetic mice, exemplified by greater glucose tolerance test performance and increased glycogen synthesis. Overexpression of caveolin-3 in hepatic cells in vitro led to increased activation of insulin receptors, as well as IRS-1 and Akt, at physiological concentrations of insulin. Our findings suggest that caveolin gene transfer to the liver enhances insulin receptor signal and mimics insulin action. Less

Report

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

    (3 results)

All 2004

All Journal Article (3 results)

  • [Journal Article] Insulin resistance in skeletal muscles of caveolin-3-null mice2004

    • Author(s)
      Jin Oshikawa
    • Journal Title

      Proc Natl Acad Sci USA 101(34)

      Pages: 12670-12675

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Insulin resistance in skeletal muscles of caveolin-3-null mice2004

    • Author(s)
      Oshikawa, Jin, Otsu, Koji, Toya, Yoshiyuki, Tsunematsu, Takashi, Hankins, Raleigh, Kawabe, Jun-ichi, Minamisawa, Susumu, Umemura, Satoshi, Hagiwara Yasuko, Ishikawa, Yoshihiro
    • Journal Title

      Proc Natl Acad Sci USA vol.101 no.34

      Pages: 12670-12675

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Insulin resistance in 5keletal muscles of caveolin-3-null mice2004

    • Author(s)
      Oshikawa J
    • Journal Title

      Proc Natl Acad Sci USA 101・34

      Pages: 12670-12675

    • Related Report
      2004 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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