Role of the forkhead protein FoxO1 in β cell compensation to insulin resistance
Role of the forkhead protein FoxO1 in β cell compensation to insulin resistance
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DOI：
10.1172/jci24967
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发表时间：
2006-03-01
影响因子：
15.9
通讯作者：
Accili, D
中科院分区：
文献类型：
--
作者：
Okamoto, H;Hribal, ML;Accili, D
糖尿病与β细胞功能缺陷和β细胞质量改变有关。调节β细胞群及其对胰岛素抵抗的适应的机制尚不清楚。目前还不清楚代偿性β细胞增生是通过现有β细胞的增殖还是通过嵌入导管上皮中的祖细胞的新生来实现的。我们已经使用转基因小鼠表达的叉头-O 1转录因子（FoxO 1）的突变形式在胰腺导管和内分泌β细胞，以评估这2个区室胰岛扩张的贡献。我们表明，突变FoxO 1转基因阻止β细胞复制2 β细胞增生模型，1由于外周胰岛素抵抗（胰岛素受体转基因敲除）和1由于IGF 2（弹性蛋白酶-IGF 2转基因）的异位局部表达，而不影响胰岛素分泌。相反，我们未能检测到FoxO 1转基因对导管周围β细胞数量的特定影响。我们认为β细胞对胰岛素抵抗的补偿是现有β细胞对生长因子信号传导的增殖反应，需要FoxO 1核排斥。
Diabetes is associated with defective beta cell function and altered beta cell mass. The mechanisms regulating beta cell mass and its adaptation to insulin resistance are unknown. It is unclear whether compensatory beta cell hyperplasia is achieved via proliferation of existing beta cells or neogenesis from progenitor cells embedded in duct epithelia. We have used transgenic mice expressing a mutant form of the forkhead-O1 transcription factor (FoxO1) in both pancreatic ductal and endocrine beta cells to assess the contribution of these 2 compartments to islet expansion. We show that the mutant FoxO1 transgene prevents beta cell replication in 2 models of beta cell hyperplasia, 1 due to peripheral insulin resistance (Insulin receptor transgenic knockouts) and 1 due to ectopic local expression of IGF2 (Elastase-IGF2 transgenics), without affecting insulin secretion. In contrast, we failed to detect a specific effect of the FoxO1 transgene on the number of periductal beta cells. We propose that beta cell compensation to insulin resistance is a proliferative response of existing beta cells to growth factor signaling and requires FoxO1 nuclear exclusion.