FoxO1 Gain of Function in the Pancreas Causes Glucose Intolerance, Polycystic Pancreas, and Islet Hypervascularization
FoxO1 Gain of Function in the Pancreas Causes Glucose Intolerance, Polycystic Pancreas, and Islet Hypervascularization
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DOI：
10.1371/journal.pone.0032249
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发表时间：
2012-02-23
期刊：
影响因子：
3.7
通讯作者：
Kitamura, Tadahiro
中科院分区：
文献类型：
--
作者：
Kikuchi, Osamu;Kobayashi, Masaki;Kitamura, Tadahiro
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单倍体缺陷在IRS2敲除小鼠中恢复了β细胞质量并挽救了糖尿病。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）。TG小鼠的糖耐量受损，其中一些确实因β细胞质量减少而患上糖尿病，这与β细胞中Pdx1和MafA的减少有关。我们还观察到TG小鼠胰管上皮细胞的增殖增加，一些小鼠随着年龄的增长出现了多囊胰腺。此外，由于β细胞中VEGF-A表达增加，TG小鼠表现出胰岛血管增生。我们发现FoxO1与VEGF-A启动子结合并调节β细胞中VEGF-A的转录。我们认为胰腺中fox01活性的失调可能导致糖尿病和胰腺囊肿的发生。
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 beta 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 beta cell mass, which is associated with decreased Pdx1 and MafA in beta 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 beta cells. We found FoxO1 binds to the VEGF-A promoter and regulates VEGF-A transcription in beta cells. We propose that dysregulation of FoxO1 activity in the pancreas could account for the development of diabetes and pancreatic cysts.