2006 Fiscal Year Final Research Report Summary
Regulation of pancreatic beta-cell neogenesis by cell cycle inhibitor p16INK4a
| Project/Area Number |
17590933
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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 |
UCHIDA Tohru Kobe University, Graduate School of Medicine, Assistant Professor, 大学院・医学系研究科, 助手 (90397828)
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| Project Period (FY) |
2005 – 2006
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| Keywords | Type 2 diabetes / Beta-cell neogenesis / Cell cycle / Insulin |
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| Research Abstract |
During development of type2 diabetes, cell cycle inhibitor p27^<KiP1> (p27) accumulates in the nucleus of pancreatic beta-cells, resulting in failure of compensatory proliferation against increased insulin resistance. Another cell cycle inhibitor, p16INK4a (p16), has been reported to function as a negative regulator of beta-cell proliferation in aged mice. Although I cannot clearly quantify, immunostaining revealed that p16 was slightly accumulated in the nucleus of pancreatic ductal epithelial cells, from which pancreatic beta-cells differentiates. Thus, I hypothesized p16 plays an important role in pancreatic beta-cell differentiation. Analysis of pancreas from p16^<-/->mice revealed increased islet density compared to wild type mice, resulting in increased beta-cell number. However, quantification of islet neogenesis in vivo is not possible so far, thus, I could not clearly prove my hypothesis. In the cultured cell line derived from pancreatic ductal epithelial cell, I tried to see
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the differentiation to beta-cells by changing the expression of p16 (overexpression or knock-down), however, the cells did not differentiate to pancreatic beta-cells reproductively. Insulin receptor substrate 2 expresses in both pancreatic beta cells and ductal epithelial cells, and knock-out of which results in severe diabetes by hepatic insulin resistance and decreased beta-cell number (decreasing islet density, islet size and beta-cell size). Knock-out of p27 in Irs2^<-/-> mice increased islet size without effects of islet density. On the other hand, however, knock-out of p16 in Irs2 mice increased islet density. The rate of onset of diabetes was 18/19 in Irs2^<-/->, 0/8 in Irs2^<-/-> p27^<-/->, 10/19 in Irs2^<-/-> p27^<+/->, 0/9 in Irs2^<-/-> p27^<+/-> p16^<+/-> and 9/14 in Irs2^<-/-> p16^<-/->. Therefore, p16 knock-out rescued diabetic phenotype of Irs2^<-/-> p27^<+/->mice, suggesting p16 plays an important role in the maintenance of beta-cell function by the mechanism different from p27. The precise mechanism of p16 for islet density has to be resolved in the future. Less
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Research Products
(2 results)
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[Journal Article] Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice.2005
Author(s)
Uchida T, Nakamura T, Hashimoto N, Matsuda T, Kotani K, Sakaue H, Kido Y, Hayashi Y, Nakayama KI, White MF, Kasuga M.
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Journal Title
Nat Med. 11-2
Pages: 175-82
Description
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