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ß-Cell-Targeted Expression of a Dominant-Negative Hepatocyte Nuclear Factor-1 Induces a Maturity-Onset Diabetes of the Young (MODY)3-Like Phenotype in Transgenic Mice

Division of Clinical Biochemistry, Department of Internal Medicine (K.A.H.-J., H.W., A.G., H.I., C.B.W.), and Department of Morphology ( P.L.H.), University Medical Center, 1211 Geneva 4, Switzerland

Address all correspondence and requests for reprints to: Claes B. Wollheim, Division of Clinical Biochemistry, Department of Internal Medicine, University Medical Center, 1 rue Michel-Servet, 1211 Geneva 4, Switzerland. E-mail: claes.wollheim{at}medecine.unige.ch

Mutations in the transcription factor hepatocyte nuclear factor-1 (HNF-1) cause maturity-onset diabetes of the young 3, a severe form of diabetes characterized by pancreatic ß-cell dysfunction. We have used targeted expression of a dominant-negative mutant of HNF-1 to specifically suppress HNF-1 function in ß-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 -cell to ß-cell ratio. ß-Cell ultrastructure showed signs of severe ß-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 deficiency causes ß-cell dysfunction in this disease.

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