| Project/Area Number |
11671132
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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 |
SATOH Shinobu University Hospital, Yokohama City University Assistant Professor, 医学部・附属病院, 講師 (80244424)
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| Co-Investigator(Kenkyū-buntansha) |
SEKIHARA Hisahiko School of Medicine, Yokohama City University Professor, 医学部, 教授 (80126094)
ITO Takaaki School of Medicine, Yokohama City University Associate Professor, 医学部, 助教授 (70168392)
NOGUCHI Yoshikazu School of Medicine, Yokohama City University Assistant Professor, 医学部, 講師 (50180724)
CUSHMAN Samuel w. National Institutes of Health, Chief
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| Project Period (FY) |
1999 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2000: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Keywords | insulin resistance / adipocyte / cell differentiation / cell proliferation / glucose transporter / GLUT1 / PPAR / apoptosis / 細胞分化増殖 / 膵β細胞 / IRS / GLUT |
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| Research Abstract |
We studied the regulation of insulin targeted cell proliferation and differentiation in the insulin resistance ; the role of expression of glucose transporter. To investigate the role of IRS-1 in endocrine pancreatic function, we have performed in vivo experiments of islet function in mice with knockout mutations in Insulin Receptor Substrate (IRS)-1 (IRS-1-/-), as well as in vitro studies on isolated islets. We found that immunostaining for GLUT2 was remarkably reduced in the beta-cells of IRS-1-/- islets. In pancreatic beta-cells, two types of granules can be distinguished by electron microscopy : mature granules with a dense core and immature granules with lightly stained content. The proportion of light granules in IRS-1-/- islets was increased and that of dark granules decreased in comparison with wild-type islets. These studies indicate that IRS-1 deficiency leads to reduced GLUT2 expression and insulin response to glucose. Thus, IRS-1 plays unique roles in beta-cell development and function. Heterozygous PPAR gamma-deficient mice were protected from the development of insulin resistance due to adipocyte hypertrophy under a high-fat diet. These phenotypes were abrogated by PPAR gamma agonist treatment. Heterozygous PPAR gamma-deficient mice showed overexpression and hypersecretion of leptin despite the smaller size of adipocytes and decreased fat mass, which may explain these phenotypes at least in part. This study reveals a hitherto unpredicted role for PPAR gamma in high-fat diet-induced obesity due to adipocyte hypertrophy and insulin resistance, which requires both alleles of PPAR gamma.
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