| Project/Area Number |
16590883
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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 | Kobe University |
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Principal Investigator |
KIDO Yoshiaki Kobe University, Graduate School of Medicine, Assistant Professor, 大学院・医学系研究科, 助手 (10335440)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2004: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Keywords | Diabetes mellitus / pancreatic β cell / PDK1 / proliferation / PDK-1 |
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| Research Abstract |
Impaired insulin secretion is an important feature of type 2 diabetes mellitus, a condition whose prevalence is increasing worldwide. The total mass of islets of Langerhans is also reduced in individuals with type 2 diabetes^1, possibly contributing to the pathogenesis of this condition. Although the regulation of islet mass is complex, recent studies have suggested the importance of a signaling pathway that includes the insulin or insulin-like growth factor-1 (IGF-1) receptors, insulin receptor substrate (IRS), and phosphatidylinositol (PI) 3-kinase^<2-4>. 3-Phosphoinositide-dependent protein kinase 1 (PDK1) is a serine-threonine kinase that mediates signaling downstream of PI 3-kinase. We show that mice that lack PDK1 specifically in pancreatic β cells (βPDK1^<-/-> mice) develop progressive hyperglycemia as a result of a loss of islet mass. The mice manifest reductions in islet density as well as in the number and size of β cells. The decrease in β-cell number appeared to be due both to a decreased rate of proliferation and to an increased susceptibility to apoptosis. Haploinsufficiency of the gene for the transcription factor Foxo1 resulted in a marked increase in the number, but not in the size, of β cells as well as in restoration of glucose homeostasis in βPDK1^<-/-> mice. These results suggest that PDK1 plays an important role in maintenance of pancreatic β-cell mass and glucose homeostasis.
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