Hagenfeldt-Johansson K A, Herrera P L, Wang H, Gjinovci A, Ishihara H, Wollheim C B
Division of Clinical Biochemistry, Department of Internal Medicine, University Medical Center, 1211 Geneva 4, Switzerland.
Endocrinology. 2001 Dec;142(12):5311-20. doi: 10.1210/endo.142.12.8592.
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.
转录因子肝细胞核因子-1α（HNF-1α）的突变会导致青年发病的成年型糖尿病3型，这是一种以胰岛β细胞功能障碍为特征的严重糖尿病形式。我们利用HNF-1α显性负性突变体的靶向表达，特异性抑制转基因小鼠β细胞中的HNF-1α功能。我们发现，表达突变蛋白的雄性小鼠在6周龄时就明显出现糖尿病，而雌性小鼠则表现出葡萄糖不耐受。转基因雄性小鼠在体内和灌注胰腺中均检测到葡萄糖刺激的胰岛素分泌受损。糖尿病动物的胰腺胰岛素含量显著降低，而胰高血糖素含量增加。出生后胰岛发育发生改变，α细胞与β细胞的比例增加。β细胞超微结构显示出严重β细胞损伤的迹象，包括线粒体肿胀。这种青年发病的成年型糖尿病3型动物模型应有助于进一步阐明HNF-1α缺乏导致该疾病中β细胞功能障碍的机制。
