Metabolic diapause in pancreatic β-cells expressing a gain-of-function mutant of the forkhead protein Foxo1
Metabolic diapause in pancreatic β-cells expressing a gain-of-function mutant of the forkhead protein Foxo1
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DOI：
10.1074/jbc.m606118200
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发表时间：
2007-01-05
影响因子：
4.8
通讯作者：
Accili, Domenico
中科院分区：
文献类型：
--
作者：
Buteau, Jean;Shlien, Adam;Accili, Domenico
糖尿病与胰腺细胞功能和质量下降有关。目前尚不清楚糖尿病治疗的目的是恢复β细胞的性能/质量，还是诱导“β细胞休息”以防止进一步恶化。转录因子Foxo1保护β细胞免受高血糖引起的氧化应激，并阻止胰岛素抵抗状态下的β细胞复制。在这里，我们表明这些综合效应与参与糖酵解、一氧化氮合成、G蛋白偶联受体信号传导和离子运输的基因的协同抑制有关。相反，Foxo1增加了几种神经递质受体的表达，并且无法调节秀丽隐杆线虫和果蝇研究中预测的靶基因。功能分析显示，过表达Foxo1的β细胞葡萄糖利用和胰岛素分泌减少。我们提出了“代谢滞育”的定义，Foxo1诱导的变化，以保护β细胞免受氧化应激。这些数据为β细胞休息作为糖尿病治疗目标的概念提供了遗传学基础。
Diabetes is associated with decreased pancreatic beta-cell function and mass. It is unclear whether diabetes treatment should aim at restoring beta-cell performance/mass or at inducing "beta-cell rest" to prevent further deterioration. The transcription factor Foxo1 protects beta-cells against oxidative stress induced by hyperglycemia and prevents beta-cell replication in insulin-resistant states. Here we show that these combined effects are associated with a concerted repression of genes involved in glycolysis, nitric-oxide synthesis, G protein-coupled receptor signaling, and ion transport. Conversely, Foxo1 increases expression of several neurotransmitter receptors and fails to regulate target genes predicted from Caenorhabditis elegans and Drosophila studies. Functional analyses show decreased glucose utilization and insulin secretion in beta-cells overexpressing Foxo1. We propose the definition of "metabolic diapause" for the changes induced by Foxo1 to protect beta-cells against oxidative stress. The data provide genetic underpinning for the concept of beta-cell rest as a treatment goal in diabetes.