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

细胞周期抑制剂 p16INK4a 对胰腺 β 细胞新生的调节

• 批准号: 17590933
• 负责人: UCHIDA Tohru
• 金额: $ 2.24万
• 依托单位: Kobe University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590933/
• 关键词: Type 2 diabetes; Beta-cell neogenesis; Cell cycle; Insulin

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 … More 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

在2型糖尿病的发展过程中，细胞周期抑制因子p27^&lt；kip1&gt；(P27)积聚在胰岛β细胞的胞核中，导致代偿性增殖不能抵抗胰岛素抵抗的增加。据报道，另一种细胞周期抑制因子p16INK4a(P16)对老年小鼠的β细胞增殖具有负面调节作用。虽然我不能清楚地定量，但免疫染色显示p16在胰腺导管上皮细胞的细胞核中略有积聚，胰腺β细胞从中分化。因此，我推测p16在胰岛β细胞分化中起重要作用。对p16^&lt；-/-&gt；小鼠胰腺的分析显示，与野生型小鼠相比，胰岛密度增加，导致β细胞数量增加。然而，到目前为止，还不可能对体内新生的胰岛进行量化，因此，我无法清楚地证明我的假设。在培养的胰腺导管上皮细胞系中，我试图看到…更多的是通过改变p16的表达(过表达或下调)来向胰岛β细胞分化，然而，细胞不能向胰岛β细胞繁殖分化。胰岛素受体底物2在胰岛β细胞和导管上皮细胞中均有表达，并通过敲除该底物导致肝脏胰岛素抵抗和β细胞数量减少(胰岛密度、胰岛大小和β细胞大小减少)而导致严重的糖尿病。在Irs2^&lt；-/-&gt；小鼠中，p27基因敲除增加了胰岛大小，而不受胰岛密度的影响。然而，另一方面，在Irs2小鼠中，p16基因的敲除增加了胰岛密度。糖尿病的发病率分别为18/19、0/8、10/19、0/14和9/14。因此，p16基因敲除拯救了Irs2^&lt；-/-&gt；p27^&lt；+/-&gt；小鼠的糖尿病表型，提示p16通过与p27不同的机制在维持β细胞功能中发挥重要作用。P16对胰岛密度的确切作用机制有待于进一步研究。较少

项目成果

Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice

• DOI: 10.1038/nm1187
• 发表时间: 2005-01
• 期刊: Nature Medicine
• 影响因子: 82.9
• 作者: T. Uchida;Takehiro Nakamura;Naoko Hashimoto;Tomokazu Matsuda;K. Kotani;H. Sakaue;Y. Kido;Y. Hayashi;K. Nakayama;M. White;M. Kasuga