The MODY1 gene HNF-4α regulates selected genes involved in insulin secretion
The MODY1 gene HNF-4α regulates selected genes involved in insulin secretion
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DOI：
10.1172/jci22365
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发表时间：
2005-04-01
影响因子：
15.9
通讯作者：
Kaestner, KH
中科院分区：
文献类型：
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作者：
Gupta, RK;Vatamaniuk, MZ;Kaestner, KH
编码肝细胞核因子-4 α（HNF-4 α）的基因突变导致青年人成熟型糖尿病（MODY）。为了确定HNF-4a对体内β细胞维持葡萄糖稳态的贡献，我们推导出HNF-4a的条件性敲除。使用Cre-loxP系统。令人惊讶的是，β细胞中HNF-4 α的缺失导致禁食和进食小鼠的高胰岛素血症，但矛盾的是也导致葡萄糖耐量受损。胰岛灌流和钙成像研究显示突变β细胞对葡萄糖和磺脲类药物刺激的异常反应。这些表型可以部分解释为钾通道亚基Kir6.2的表达减少60%。我们使用共转染实验证明Kir6.2基因是HNF-4 α的转录靶点。我们的数据提供了HNF-4a的遗传证据。在胰腺β细胞中是调节依赖于ATP依赖性钾通道的胰岛素分泌途径所必需的。
Mutations in the gene encoding hepatocyte nuclear factor-4 alpha (HNF-4 alpha) result in maturity-onset diabetes of the young (MODY). To determine the contribution of HNF-4a to the maintenance of glucose homeostasis by the beta cell in vivo, we derived a conditional knockout of HNF-4a. using the Cre-loxP system. Surprisingly, deletion of HNF-4 alpha in beta cells resulted in hyperinsulinemia in fasted and fed mice but paradoxically also in impaired glucose tolerance. Islet perifusion and calcium-imaging studies showed abnormal responses of the mutant beta cells to stimulation by glucose and sulfonylureas. These phenotypes can be explained in part by a 60% reduction in expression of the potassium channel subunit Kir6.2. We demonstrate using cotransfection assays that the Kir6.2 gene is a transcriptional target of HNF-4 alpha. Our data provide genetic evidence that HNF-4a. is required in the pancreatic beta cell for regulation of the pathway of insulin secretion dependent on the ATP-dependent potassium channel.