Department of Medicine, University of Chicago, Chicago, IL
Department of Medicine, University of Chicago, Chicago, IL.
Diabetes. 2014 Aug;63(8):2744-50. doi: 10.2337/db13-1513. Epub 2014 Mar 21.
Mutations in pancreatic duodenal homeobox-1 (PDX1) are associated with diabetes in humans. Pdx1-haploinsufficient mice develop diabetes due to an increase in β-cell death leading to reduced β-cell mass. For definition of the molecular link between Pdx1 deficiency and β-cell death, Pdx1-haploinsufficient mice in which the genes for the BH3-only molecules Bim and Puma had been ablated were studied on a high-fat diet. Compared with Pdx1(+/-) mice, animals haploinsufficient for both Pdx1 and Bim or Puma genes showed improved glucose tolerance, enhanced β-cell mass, and reduction in the number of TUNEL-positive cells in islets. These results suggest that Bim and Puma ablation improves β-cell survival in Pdx1(+/-) mice. For exploration of the mechanisms responsible for these findings, Pdx1 gene expression was knocked down in mouse MIN6 insulinoma cells resulting in apoptotic cell death that was found to be associated with increased expression of BH3-only molecules Bim and Puma. If the upregulation of Bim and Puma that occurs during Pdx1 suppression was prevented, apoptotic β-cell death was reduced in vitro. These results suggest that Bim and Puma play an important role in β-cell apoptosis in Pdx1-deficient diabetes.
胰腺十二指肠同源盒-1 (PDX1) 突变与人类糖尿病有关。由于β细胞死亡增加导致β细胞数量减少，Pdx1 杂合不足的小鼠会发生糖尿病。为了定义 Pdx1 缺乏与β细胞死亡之间的分子联系，研究了在高脂肪饮食下缺失 BH3 仅分子 Bim 和 Puma 基因的 Pdx1 杂合不足小鼠。与 Pdx1(+/-) 小鼠相比，同时缺失 Pdx1 和 Bim 或 Puma 基因的杂合不足动物表现出改善的葡萄糖耐量、增强的β细胞质量以及胰岛中 TUNEL 阳性细胞数量减少。这些结果表明 Bim 和 Puma 的缺失可改善 Pdx1(+/-) 小鼠的β细胞存活。为了探究这些发现的机制，在小鼠 MIN6 胰岛素瘤细胞中敲低 Pdx1 基因表达导致凋亡性细胞死亡，发现这与 BH3 仅分子 Bim 和 Puma 的表达增加有关。如果阻止 Pdx1 抑制期间发生的 Bim 和 Puma 的上调，则体外的β细胞凋亡减少。这些结果表明 Bim 和 Puma 在 Pdx1 缺乏型糖尿病的β细胞凋亡中发挥重要作用。
