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