Tissue-specific deletion of Foxa2 in pancreatic β cells results in hyperinsulinemic hypoglycemia
Tissue-specific deletion of Foxa2 in pancreatic β cells results in hyperinsulinemic hypoglycemia
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DOI：
10.1101/gad.901601
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发表时间：
2001-07-01
影响因子：
10.5
通讯作者：
Kaestner, KH
中科院分区：
文献类型：
--
作者：
Sund, NJ;Vatamaniuk, MZ;Kaestner, KH
我们已经使用条件性基因切除来揭示翼形螺旋转录因子Foxa 2（以前的HNF-3 β）在胰腺β细胞分化和代谢中的戏剧性和不可预测的作用。在β细胞中特异性缺乏Foxa 2的小鼠（Foxa 2（loxP/loxP）; Ins.Cre小鼠）是严重的低血糖，并且显示出响应于葡萄糖和氨基酸的胰岛素分泌失调。这种在严重低血糖情况下胰岛素分泌过多的现象与家族性高胰岛素血症的病理生理学和分子学特征相似。我们已经鉴定了β细胞ATP敏感性K+通道（K-ATP）的两个亚基，其是与家族性高胰岛素血症相关的最频繁突变的基因，作为胰岛中的新型Foxa 2靶点。Foxa2（loxP/loxP）; Ins.Cre小鼠将作为研究β细胞对胰岛素分泌调节的独特模型，并提示人FOXA 2是家族性高胰岛素血症的候选基因。
We have used conditional gene ablation to uncover a dramatic and unpredicted role for the winged-helix transcription factor Foxa2 (formerly HNF-3 beta) in pancreatic beta -cell differentiation and metabolism. Mice that lack Foxa2 specifically in beta cells (Foxa2(loxP/loxP); Ins.Cre mice) are severely hypoglycemic and show dysregulated insulin secretion in response to both glucose and amino acids. This inappropriate hypersecretion of insulin in the face of profound hypoglycemia mimics pathophysiological and molecular aspects of familial hyperinsulinism. We have identified the two subunits of the beta -cell ATP-sensitive K+ channel (K-ATP), the most frequently mutated genes linked to familial hyperinsulinism, as novel Foxa2 targets in islets. The Foxa2(loxP/loxP); Ins.Cre mice will serve as a unique model to investigate the regulation of insulin secretion by the beta cell and suggest the human FOXA2 as a candidate gene for familial hyperinsulinism.