| Project/Area Number |
17390261
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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 | the University of Tokyo |
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Principal Investigator |
TOBE Kazuyuki The University of Tokyo, Faculty of Medicine, Lecturer, 医学部附属病院, 講師 (30251242)
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| Co-Investigator(Kenkyū-buntansha) |
KADOWAKI Takashi The University of Tokyo, Faculty of Medicine, Professor, 医学部附属病院, 教授 (30185889)
SUZUKI Ryo The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (20396732)
NODA Mitsuhiko Okinaka Memorial Institute for Medical Research, Researcher, 研究員 (90237850)
KUBOTA Naoto The University of Tokyo, Faculty of Medicine, Visiting Instructor, 医学部附属病院, 客員教員 (50396719)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥15,400,000 (Direct Cost: ¥15,400,000)
Fiscal Year 2006: ¥5,900,000 (Direct Cost: ¥5,900,000)
Fiscal Year 2005: ¥9,500,000 (Direct Cost: ¥9,500,000)
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| Keywords | pancreatic β cell / β cell proliferation / IRS / IRS-2 / High Fat Diet / insulin secretion / diabetes / 増殖 |
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| Research Abstract |
Insulin receptor substrate (IRS)^1-1 and IRS-2 are two major substrates for insulin receptor tyrosine kinase and insulin-like growth factor (IGF) receptor tyrosine kinase. Irs1^<-/-> mice have insulin-resistant skeletal muscles but do not develop diabetes because β-cells are able to undergo hyperplasia and secrete more insulin to compensate for the insulin resistance. In contrast, Irs2^<-/-> mice develop diabetes because β-cells failed to undergo hyperplasia in response to insulin resistance due to obesity and insulin signaling defects in the liver. We also developed mice lacking Irs2 in β-cells and the hypothalamus by crossing rat insulin II promoter (RIP)-Cre and irs2/loxP mice. The conditional knockout mice from either laboratory commonly show hyperglycemia with β-cell mass reduction and obesity. In our animals, which we designated βHT-IRS2 mice, β-cell proliferation is significantly decreased. These studies point to the conclusion that IRS-2 is crucial to the regulation of β-cell mass in adult animals. We also showed marked induction of β-cell growth and Irs2 expression in the islets of high fat diet-fed wild-type mice. Since we observed reduced expression of Irs2 protein and attenuated β-cell growth in the islets of high fat diet-fed glucokinase(+/-) mice, we conclude that Gck and Irs2 are critical requirements for β-cell hyperplasia to occur in response to high fat diet-induced insulin resistance.
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