Glucose regulates Foxo1 through insulin receptor signaling in the pancreatic islet β-cell
Glucose regulates Foxo1 through insulin receptor signaling in the pancreatic islet β-cell
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DOI：
10.2337/db05-0678
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发表时间：
2006-06-01
期刊：
影响因子：
7.7
通讯作者：
Permutt, M. Alan
中科院分区：
文献类型：
--
作者：
Martinez, Sara C.;Cras-Meneur, Corentin;Permutt, M. Alan
葡萄糖至少部分地通过胰岛素信号传导下游的磷脂酰肌醇3-激酶（PI 3 K）/A-kt途径控制胰岛β细胞质量和功能。Foxo蛋白是已知在其他组织中受Akt活化负调控的转录因子，影响增殖和代谢。在这项研究中，我们测试的假设，葡萄糖调节Foxo 1活性的β细胞通过自分泌/旁分泌作用释放胰岛素的受体。小鼠胰岛素瘤细胞（MIN 6）因葡萄糖（5 mmol/l）而饥饿过夜，然后再用葡萄糖（25 mmol/l）补充，导致快速的Foxo I磷酸化（30分钟，P < 0.05，与未处理的相比）。这种葡萄糖反应被证明是时间（0.5-2小时）和剂量（5-30 mmol/l）依赖性的。抑制剂的使用表明，葡萄糖诱导的Foxo 1磷酸化依赖于去极化，钙内流和PI 3 K信号。此外，葡萄糖浓度在生理范围（2.5-20 mmol/l）内的增加导致Foxo 1的核至细胞质易位。在胰岛素受体敲低细胞系中，葡萄糖再喂养后Foxo 1的磷酸化和易位被消除，表明葡萄糖效应主要通过胰岛素受体介导。通过IGF结合蛋白-1启动子荧光素酶测定，观察到Foxo 1的活性随着葡萄糖浓度的降低而增加。饥饿的MIN 6细胞确定了一个假定的Foxo 1的目标，Chop，和Choppromoter荧光素酶检测共转染Foxo 1的存在下支持这一假设。这些观察结果的重要性在于，β细胞中的营养改变与Foxo 1转录活性的变化相关，并且这些变化主要通过葡萄糖刺激的胰岛素分泌介导，胰岛素分泌通过其自身的受体起作用。
Glucose controls islet beta-cell mass and function at least in part through the phosphatidylinositol 3-kinase (PI3K)/A-kt pathway downstream of insulin signaling. The Foxo proteins, transcription factors known in other tissues to be negatively regulated by Akt activation, affect proliferation and metabolism. In this study, we tested the hypothesis that glucose regulates Foxo1 activity in the beta-cell via an autocrine/paracrine effect of released insulin on its receptor. Mouse insulinoma cells (MIN6) were starved overnight for glucose (5 mmol/l) then refed with glucose (25 mmol/l), resulting in rapid Foxo I phosphorylation (30 min, P < 0.05 vs. untreated). This glucose response was demonstrated to be time (0.5-2 h) and dose (5-30 mmol/l) dependent. The use of inhibitors demonstrated that glucose-induced Foxo1 phosphorylation was dependent upon depolarization, calcium influx, and PI3K signaling. Additionally, increases in glucose concentration over a physiological range (2.5-20 mmol/l) resulted in nuclear to cytoplasmic translocation of Foxo1. Phosphorylation and translocation of Foxo1 following glucose refeeding were eliminated in an insulin receptor knockdown cell line, indicating that the glucose effects are mediated primarily through the insulin receptor. Activity of Foxo1 was observed to increase with decreased glucose concentrations, assessed by an IGF binding protein-1 promoter luciferase assay. Starvation of MIN6 cells identified a putative Foxo1 target, Chop, and a Choppromoter luciferase assay in the presence of cotransfected Foxo1 supported this hypothesis. The importance of these observations was that nutritional alterations in the beta-cell are associated with changes in Foxo1 transcriptional activity and that these changes are predominantly mediated through glucose-stimulated insulin secretion acting through its own receptor.