Characterisation of the mouse diabetes susceptibility locus Nidd/SJL: islet cell destruction, interaction with the obesity QTL Nob1, and effect of dietary fat

Abstract

Aims/hypothesis. 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 × F1(SJL×NZO) backcross population raised on high-fat or standard diet, and describe its interaction with the obesity quantitative trait locus (QTL) Nob1. Methods. NZO × F1(SJL×NZO) 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. Conclusion/interpretation. 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. [Diabetologia (2002) 45:823-830]

Development of diabetes in obese, insulin-resistant mice: essential role of dietary carbohydrate in beta cell destruction

“…In the presence of dietary carbohydrate, an increase of dietary fat accelerated the development of diabetes (Fig. 2) [8]. Thus, obesity is absolutely required for diabetes to develop in NZO mice, although on its own it is apparently not sufficient.…”

“…With outcross populations, a threshold body weight (45 g at 12 weeks) is required for the development of diabetes [8,12,28,29]. In the presence of dietary carbohydrate, an increase of dietary fat accelerated the development of diabetes (Fig.…”

“…In the db/db mouse strain, the prevalence of diabetes can be markedly reduced by the substitution of dietary protein for carbohydrate [7], suggesting that postprandial hyperglycaemia may play a role in the pathogenesis of islet cell failure. We have previously demonstrated that dietary fat content, in combination with the presence of diabetogenic alleles, markedly increases the prevalence of diabetes in parental New Zealand Obese mice (NZO) as well as in an outcross population of NZO with the lean SJL strain [8]. The NZO mouse is an optimal model for the study of obesityassociated diabetes ('diabesity').…”

Major quantitative trait locus on chromosome 2 for glucose tolerance in diabetic SMXA-5 mouse established from non-diabetic SM/J and A/J strains

“…Since genetic and environmental factors can be strictly controlled when inbred animal models are used, such models are invaluable for the dissection of complex diseases. Loci contributing to type 2 diabetes and related traits in diabetic animal models have been reported using quantitative trait locus (QTL) mapping analyses (GK rat [2,3], OLETF rat [2,[4][5][6][7], SDT rat [8], NSY mouse [9], NZO mouse [10,11], TSOD mouse [12], KK mouse [13], KK-Ay mouse [14,15] and TH mouse [16]). …”

Skeletal muscle mitochondrial uncoupling prevents diabetes but not obesity in NZO mice, a model for polygenic diabesity

“…NZO mice have been used in outcross studies aimed to locate genes responsible for obesity, insulin resistance and diabetes (Joost 2010;Joost and Schurmann 2014;Leiter et al 1998). Quantitative trait loci (QTLs) affecting adiposity and blood glucose have been identified on a number of chromosomes and different loci (Plum et al 2002;Taylor et al 2001;Vogel et al 2009Vogel et al , 2012Vogel et al , 2013 confirming the polygenic nature of obesity and diabetes development in this mouse model. On a high-fat diet NZO mice exhibit hypertension and hypercholesterolemia in addition to obesity, hyperinsulinemia and hyperglycemia (Joost and Schurmann 2014;Ortlepp et al 2000).…”