| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
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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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