The lack of caveolin-3, muscle-specific subtype of caveolin, leeds to the development of insulin resistance
| Project/Area Number |
15590951
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Metabolomics
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| Research Institution | Yokohama City University |
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Principal Investigator |
TOYA Yoshiyuki Yokohama City University, Hospital, Assistant Professor, 医学部附属病院, 助教授 (30237143)
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| Co-Investigator(Kenkyū-buntansha) |
ISHIKAWA Yoshihiro Yokohama City University, School of Medicine, Professor, 大学院・医学研究科, 教授 (40305470)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| 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)
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| Keywords | insulin resistance / insulin signal / caveolin / skeletal muscle / glycogen / type 2 diabetes / knockout mouse / gene transfer / インスリン |
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| 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
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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
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Report
(3 results)
Research Products
(3 results)
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[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
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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
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