Dominant-negative effects of a novel mutated Ins2 allele causes early-onset diabetes and severe beta-cell loss in Munich Ins2C95S mutant mice.
The novel diabetic mouse model Munich Ins2(C95S) was discovered within the Munich N-ethyl-N-nitrosourea mouse mutagenesis screen. These mice exhibit a T-->A transversion in the insulin 2 (Ins2) gene 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 compared with 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 homeostasis model assessment (HOMA) beta-cell indices of heterozygous mutants were significantly lower than those of wild-type littermates. The initial blood glucose decrease during an 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 compared with wild-type mice. Electron microscopy of the beta-cells of male mutants showed virtually no secretory insulin granules, the endoplasmic reticulum was severely enlarged, and mitochondria appeared swollen. Thus, Munich Ins2(C95S) mutant mice are considered a valuable model to study the mechanisms of beta-cell dysfunction and death during the development of diabetes.
Herbach
Nadja
N
Institute of Veterinary Pathology, University of Munich, Munich, Germany. herbach@patho.vetmed.uni-muenchen.de
Rathkolb
Birgit
B
Kemter
Elisabeth
E
Pichl
Lisa
L
Klaften
Matthias
M
de Angelis
Martin Hrabé
MH
Halban
Philippe A
PA
Wolf
Eckhard
E
Aigner
Bernhard
B
Wanke
Ruediger
R
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002874:Chromosome Mapping; D004247:DNA / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D006580:Genetic Carrier Screening; D006720:Homozygote; D006801:Humans; D007328:Insulin / Q000097:blood / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000473:pathology*; D051379:Mice; D008809:Mice, Inbred C3H; D010179:Pancreas / Q000473:pathology; D015995:Prevalence
D001786:Blood Glucose; D007328:Insulin; D004247:DNA