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

Mutations in the transcription factor hepatocyte nuclear factor-1 alpha (HN F-1 alpha) cause maturity-onset diabetes of the young 3, a severe form of d iabetes characterized by pancreatic beta -cell dysfunction. We have used ta rgeted expression of a dominant-negative mutant of HNF-1 alpha to specifica lly suppress HNF-1 alpha function in beta -cells of transgenic mice. We sho w 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 b eta -cell ratio. beta -Cell ultrastructure showed signs of severe beta -cel l damage, including mitochondrial swelling. This animal model of maturity-o nset diabetes of the young 3 should be useful for the further elucidation o f the mechanism by which HNF-1 alpha deficiency causes beta -cell dysfuncti on in this disease.