β-cell-targeted expression of a dominant-negative hepatocyte nuclear factor-1α induces a maturity-onset diabetes of the young (MODY)3-like phenotype in transgenic mice
β-cell-targeted expression of a dominant-negative hepatocyte nuclear factor-1α induces a maturity-onset diabetes of the young (MODY)3-like phenotype in transgenic mice
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DOI：
10.1210/en.142.12.5311
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发表时间：
2001-12-01
期刊：
影响因子：
4.8
通讯作者：
Wollheim, CB
中科院分区：
文献类型：
--
作者：
Hagenfeldt-Johansson, KA;Herrera, PL;Wollheim, CB
转录因子肝细胞核因子-1 α (HNF-1 α)的突变导致年轻人的成熟型糖尿病，这是一种以胰腺β细胞功能障碍为特征的严重糖尿病。我们使用靶向表达HNF-1 α的显性阴性突变体来特异性抑制转基因小鼠β细胞中的HNF-1 α功能。我们发现，表达突变蛋白的雄性在6周内明显患上糖尿病，而雌性则表现出葡萄糖耐受不良。在体内和灌注胰腺中检测到，转基因雄性小鼠表现出葡萄糖刺激的胰岛素分泌受损。糖尿病动物胰腺胰岛素含量明显降低，胰高血糖素含量明显升高。出生后胰岛发育发生改变，α细胞与β细胞的比例增加。细胞超微结构显示严重的细胞损伤迹象，包括线粒体肿胀。该成熟型糖尿病的动物模型有助于进一步阐明HNF-1 α缺乏导致该疾病中β细胞功能障碍的机制。
Mutations in the transcription factor hepatocyte nuclear factor-1 alpha (HNF-1 alpha) cause maturity-onset diabetes of the young 3, a severe form of diabetes characterized by pancreatic beta -cell dysfunction. We have used targeted expression of a dominant-negative mutant of HNF-1 alpha to specifically suppress HNF-1 alpha function in beta -cells of transgenic mice. We show that males expressing the mutant protein became overtly diabetic within 6 wk of age, whereas females displayed glucose intolerance. Transgenic males exhibited impaired glucose-stimulated insulin secretion, detected both in vivo and in the perfused pancreas. Pancreatic insulin content was markedly decreased in diabetic animals, whereas the glucagon content was increased. Postnatal islet development was altered, with an increased alpha -cell to beta -cell ratio. beta -Cell ultrastructure showed signs of severe beta -cell damage, including mitochondrial swelling. This animal model of maturity-onset diabetes of the young 3 should be useful for the further elucidation of the mechanism by which HNF-1 alpha deficiency causes beta -cell dysfunction in this disease.