The molecular mechanism by which FoxO1 regulates islet vascularization and compensative beta cell proliferation

遗传学研究表明，胰腺中胰岛素/IGF-1信号的消融会导致糖尿病。Foxo1是胰岛素/IGF-1信号通路的下游转录因子。我们先前报道FoxO1单倍体功能不全已恢复。IRS2基因敲除小鼠的细胞量和挽救的糖尿病。然而，目前仍不清楚胰腺中的FoxO1失调是否可能是糖尿病的原因。为了验证这一假设，我们产生了在胰腺(TG)中高表达结构性活性FoxO1的转基因小鼠。转基因小鼠的糖耐量受损，其中一些确实由于糖耐量减少而患上糖尿病。细胞质量，这与Pdx1和Mafa的减少有关。细胞。我们还观察到，由于血管内皮细胞生长因子-A的表达增加，转基因小鼠的胰岛血管增多。细胞。我们进行了染色质免疫沉淀(ChIP)实验，结果显示FoxO1与血管内皮生长因子-A启动子结合。我们还在荧光素酶检测中发现，FoxO1调节着血管内皮生长因子-A的转录。细胞。当腺病毒过表达FoxO1时，TC3细胞中的VEGF-AmRNA水平升高。尽管严重减少了。细胞、血浆胰岛素水平和血糖水平以及葡萄糖耐量都受到了轻微的损害。我们推测这是由于转基因小鼠血管内皮生长因子-A表达增加和胰岛血管增多所致。我们认为胰腺中的FoxO1在糖代谢的调节中起着重要作用。

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 . 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 . cell mass, which is associated with decreased Pdx1 and MafA in . cells. We also observed that TG mice have islet hypervascularities due to increased VEGF-A expression in . cells. We performed chromatin immunoprecipitation (ChIP) assays and showed that FoxO1 binds to the VEGF-A promoter. We also showed in luciferase assays that FoxO1 regulates VEGF-A transcription in . cells. When FoxO1 is over expressed by adenovirus, VEGF-A mRNA level was increased in .TC3 cells. Despite severe reduction of . cells, plasma insulin levels and blood glucose levels as well as glucose tolerance were marginally impaired. We suppose this is due to increased VEGF-A expression and increased islets vascularity in TG mice. We propose that FoxO1 in pancreas plays important roles in the regulation of glucose metabolism.