title: Beta-cell-targeted expression of a dominant-negative hepatocyte nuclear factor-1 alpha induces a maturity-onset diabetes of the young (MODY)3-like phenotype in transgenic mice.
abstract: 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.
authors.affiliation: Division of Clinical Biochemistry, Department of Internal Medicine, University Medical Center, 1211 Geneva 4, Switzerland.
authors.forename: K A
authors.initials: KA
authors.lastname: Hagenfeldt-Johansson
authors.forename: P L
authors.initials: PL
authors.lastname: Herrera
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.forename: A
authors.initials: A
authors.lastname: Gjinovci
authors.forename: H
authors.initials: H
authors.lastname: Ishihara
authors.forename: C B
authors.initials: CB
authors.lastname: Wollheim
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D018390:Gene Targeting; D005799:Genes, Dominant; D005934:Glucagon / Q000378:metabolism; D018149:Glucose Intolerance / Q000235:genetics; D051273:Glucose Transporter Type 2; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D007328:Insulin / Q000378:metabolism; D007329:Insulin Antagonists / Q000494:pharmacology; D007515:Islets of Langerhans / Q000502:physiology* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009154:Mutation / Q000502:physiology; D009687:Nuclear Proteins; D010179:Pancreas / Q000378:metabolism; D010641:Phenotype; D012727:Sex Characteristics; D014157:Transcription Factors / Q000235:genetics* / Q000494:pharmacology
chemical_list: D004268:DNA-Binding Proteins; D051273:Glucose Transporter Type 2; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C496496:Hnf1b protein, mouse; D007328:Insulin; D007329:Insulin Antagonists; D009004:Monosaccharide Transport Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D005934:Glucagon