Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan.
PLoS One. 2012;7(2):e32249. doi: 10.1371/journal.pone.0032249. Epub 2012 Feb 23.
Genetic studies revealed that the ablation of insulin/IGF-1 signaling in the pancreas causes diabetes. FoxO1 is a downstream transcription factor of insulin/IGF-1 signaling. We previously reported that FoxO1 haploinsufficiency restored β cell mass and rescued diabetes in IRS2 knockout mice. However, it is still unclear whether FoxO1 dysregulation in the pancreas could be the cause of diabetes. To test this hypothesis, we generated transgenic mice overexpressing constitutively active FoxO1 specifically in the pancreas (TG). TG mice had impaired glucose tolerance and some of them indeed developed diabetes due to the reduction of β cell mass, which is associated with decreased Pdx1 and MafA in β cells. We also observed increased proliferation of pancreatic duct epithelial cells in TG mice and some mice developed a polycystic pancreas as they aged. Furthermore, TG mice exhibited islet hypervascularities due to increased VEGF-A expression in β cells. We found FoxO1 binds to the VEGF-A promoter and regulates VEGF-A transcription in β cells. We propose that dysregulation of FoxO1 activity in the pancreas could account for the development of diabetes and pancreatic cysts.
遗传研究表明，胰岛素/IGF-1 信号在胰腺中的缺失会导致糖尿病。FoxO1 是胰岛素/IGF-1 信号的下游转录因子。我们之前曾报道，FoxO1 杂合不足可恢复β细胞质量并挽救 IRS2 敲除小鼠的糖尿病。然而，FoxO1 在胰腺中的失调是否会导致糖尿病仍不清楚。为了验证这一假说，我们生成了胰腺特异性过表达组成型激活 FoxO1 的转基因小鼠（TG）。TG 小鼠表现出葡萄糖耐量受损，其中一些由于β细胞质量减少而确实发生了糖尿病，这与β细胞中 Pdx1 和 MafA 的减少有关。我们还观察到 TG 小鼠的胰腺导管上皮细胞增殖增加，并且一些小鼠随着年龄的增长出现多囊胰腺。此外，由于β细胞中 VEGF-A 的表达增加，TG 小鼠表现出胰岛高血管化。我们发现 FoxO1 与 VEGF-A 启动子结合，并调节β细胞中的 VEGF-A 转录。我们提出，胰腺中 FoxO1 活性的失调可能是糖尿病和胰腺囊肿发展的原因。
