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信号的消融导致糖尿病。fox01是胰岛素/IGF-1信号的下游转录因子。我们之前报道过fox01单倍功能不足恢复。IRS2基因敲除小鼠的细胞质量和拯救性糖尿病然而，目前尚不清楚胰腺中fox01的失调是否可能是糖尿病的原因。为了验证这一假设，我们在胰腺中产生了特异性过表达构成型活性FoxO1的转基因小鼠（TG）。甘油三酯小鼠的葡萄糖耐量受损，其中一些小鼠确实因葡萄糖含量降低而患上了糖尿病。细胞质量，这与Pdx1和MafA的减少有关。细胞。我们还观察到，由于VEGF-A表达增加，TG小鼠的胰岛血管增生。细胞。我们进行了染色质免疫沉淀（ChIP）实验，结果显示FoxO1与VEGF-A启动子结合。我们还在荧光素酶实验中发现fox01调节VEGF-A的转录。细胞。当fox01被腺病毒过表达时，VEGF-A mRNA水平升高。TC3细胞。尽管严重减少。细胞、血浆胰岛素水平和血糖水平以及葡萄糖耐量都轻微受损。我们认为这是由于TG小鼠中VEGF-A表达增加和胰岛血管性增加所致。我们认为FoxO1在胰腺的糖代谢调控中起重要作用。

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.