Regulation of pancreatic beta-cell neogenesis by cell cycle inhibitor p16INK4a

• Project/Area Number: 17590933
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kobe University
• Principal Investigator: UCHIDA Tohru Kobe University, Graduate School of Medicine, Assistant Professor, 大学院・医学系研究科, 助手 (90397828)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥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)
• Keywords: Type 2 diabetes / Beta-cell neogenesis / Cell cycle / Insulin

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 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.

Research Products

• [Journal Article] Bonner-Weir S, Sharpless NE., p16INK4a induces an age-dependent decline in islet regenerative potential. (2006)
  • Author(s): Krishnamurthy J, Ramsey MR, Ligon KL, Torrice C, Koh A
  • Journal Title: Nature 443-7110 Pages: 453-7
  • Description: 「研究成果報告書概要(欧文)」より
• [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.
  • Journal Title: Nat Med. 11-2 Pages: 175-82
  • Description: 「研究成果報告書概要(欧文)」より