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Dominant negative effects of a novel mutated Ins2 allele causes early onset diabetes mellitus and severe beta cell loss in Munich Ins2^C95S mutant mice

¹Institute of Veterinary Pathology, Veterinaerstr. 13, University of Munich, Germany
²Institute of Molecular Animal Breeding/Gene Center, Feodor-Lynenstr. 25, University of Munich, Germany
³Institute of Experimental Genetics, GSF-National Research Center for Environment and Health, Ingolstaedter Landstrasse 1, Neuherberg, Germany
⁴Department of Genetic Medicine and Development, CMU, 1 rue Michel-Servet, 1211 Geneva 4, Switzerland

Correspondence: herbach{at}patho.vetmed.uni-muenchen.de

The novel diabetic mouse model Munich Ins2^C95S was discovered within the Munich ENU mouse mutagenesis screen. These mice exhibit a TA transversion in the insulin 2 gene (Ins2) at nucleotide position 1903 in exon 3, which leads to the amino acid exchange C95S and loss of the A6-A11 intrachain disulfide bond. From 1 month of age onwards, blood glucose levels of heterozygous Munich Ins2^C95S mutant mice were significantly increased as compared to controls. The fasted and postprandial serum insulin levels of the heterozygous mutants were indistinguishable from those of wild-type littermates. However, serum insulin levels after glucose challenge, pancreatic insulin content and HOMA beta cell indices of heterozygous mutants were significantly lower than those of wild-type littermates. Initial blood glucose decrease during insulin tolerance test was lower and HOMA insulin resistance indices were significantly higher in mutant mice, indicating the development of insulin resistance in mutant mice. The total islet volume, the volume density of beta cells in the islets and the total beta cell volume of heterozygous male mutants was significantly reduced, as compared to wild-type mice. Electron microscopy of the beta cells of male mutants showed virtually no secretory insulin granules, the endoplasmatic reticulum was severely enlarged and mitochondria appeared swollen. Thus, Munich Ins2^C95S mutant mice are considered as a valuable model to study the mechanisms of beta cell dysfunction and death during the development of diabetes mellitus.

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