Characterisation of the mouse diabetes susceptibilty locus Nidd/SJL: islet cell destruction, interaction with the obesity QTL Nob1, and effect of dietary fat.
OBJECTIVE
The diabetes susceptibility locus Nidd/SJL was identified in an outcross of New Zealand obese (NZO) and lean Swiss/Jackson Laboratory mouse strain (SJL) mice. Here we characterise its effects in a NZO x F1(SJLxNZO) backcross population raised on high-fat or standard diet, and describe its interaction with the obesity quantitative trait locus (QTL) Nob1.


METHODS
NZO x F1(SJLxNZO) backcross mice were raised on a normal or high fat diet and were monitored (body weight, blood glucose, serum insulin) for 22 weeks. Genotypes of polymorphic markers were determined by PCR, and linkage analysis was done. Pancreas morphology was assessed by conventional staining and immunohistochemistry of insulin.


RESULTS
In backcross mice raised on a high-fat diet, Nidd/SJL produced hyperglycaemia (maximum likelihood of the odds (LOD) score 9.9), hypoinsulinaemia, reduction of islet-cell volume, and loss of beta cells. No effect was observed on body weight and serum insulin concentrations before the onset of hyperglycaemia. The development of diabetes in carriers of Nidd/SJL was markedly accelerated and aggravated by the obesity/hyperinsulinaemia QTL Nob1; together, these loci were responsible for approximately 90% of the diabetes observed in the backcross population. When raised on a standard diet, Nidd/SJL carriers exhibited a fivefold higher prevalence of diabetes, but Nob1 failed to enhance the effect of Nidd/SJL.


CONCLUSIONS
Diabetes in this obese mouse model is the result of an interaction of genes responsible for obesity/insulin resistance (e.g. Nob1) and islet cell failure ( Nidd/SJL). The combined diabetogenic effects of Nidd/SJL and Nob1 were markedly enhanced by a high-fat diet, whereas that of Nidd/SJL alone was independent of the dietary fat content.
Plum
L
L
Institute of Pharmacology and Toxicology, Medical Faculty, Technical University of Aachen, Aachen, Germany.
Giesen
K
K
Kluge
R
R
Junger
E
E
Linnartz
K
K
Schürmann
A
A
Becker
W
W
Joost
H-G
HG
D000818:Animals; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D003920:Diabetes Mellitus / Q000235:genetics*; D004032:Diet; D004041:Dietary Fats / Q000494:pharmacology*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006943:Hyperglycemia / Q000235:genetics; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains / Q000235:genetics; D008820:Mice, Obese / Q000235:genetics*; D009765:Obesity; D010179:Pancreas / Q000473:pathology; D040641:Quantitative Trait Loci; D013997:Time Factors
D004041:Dietary Fats; D004247:DNA