Non-Immune Islet beta cell susceptibility to failure in NODk mice

Abstract

NODk mice are congenic for the protective MHC H2k (Idd 1 locus) and unlike NOD mice do not develop autoimmune diabetes. The aim of the study was to determine if NODk β-cells have a non-immune islet beta-cell defect that may be revealed by stressing the islets with high fat diet (HFD). B10k (B10.Br mice with H2k haplotype) and Balb/c mice were used as comparator groups. Male NODk, B10k and Balb/c mice were fed chow or HF diets from 4 weeks of age for 10 weeks (short-term study) and 20 weeks (long-term study). Body weight and 9 AM fed-state blood glucose levels were measured fortnightly. At 13 and 23 weeks of age intraperitoneal glucose tolerance tests (ipGTT) were performed for both studies. NODk mice were refreshed by backcrossing on to NOD mice (NODk-REF) and preliminary experiments were performed to determine the effects of HF-feeding. NODk-REF mice were also fed chow or HF-diet from weaning, with fortnightly body weight and fedstate blood glucose measurements, and ipGTTs were performed after 9 and 20 weeks on diets. At sacrifice, the pancreases were harvested for histological assessment, including; islet morphology, islet inflammation, beta-cell apoptosis, insulin immunohistochemistry and beta-cell mass measurement. Despite excellent glucose tolerance at all ages on chow diet, HF-fed NODk mice developed diet-induced obesity, profound hyperinsulinemia and diabetes by 13 weeks of age. Severe hyperglycaemia caused several NODk mice to be euthanased prior to completing the long-term study. B10k mice had poor glucose tolerance on chow diet only, but despite some HF-diet induced excessive weight gain, they did not develop severe hyperinsulinemia or progress onto diabetes. Balb/c mice maintained excellent glucose tolerance on both diets. Analyses of the pancreas histology does not indicate that diabetes in the HF-fed NODk mice is due to insulitis. Islet beta-cell mass initially increased in HF-fed NODk mice, but finally began to decrease in the long-term cohort, accompanied by the presence of occasional apoptosis in endocrine cells in the islets of these mice. The pancreas histological features of the B10k and Balb/c mice did not indicate failure of beta-cell mass compensatory effects with HF-feeding. Many of the effects of HF-feeding of NODk mice were seen in the HF-fed NODk-REF mice, except for the development of diabetes. This suggests that the NODk mice have an additional islet beta-cell susceptibility to failure compared to the NODk-REF mice. These preliminary results indicate that a major diabetes susceptibility factor present in the NODk mice, important for type 2 diabetes (T2D) development, is not necessary for the development of type 1 diabetes (T1D). In conclusion, NODk mice are prone to a severe type 2 diabetes (T2D) phenotype when fed a HF-diet. Underlying non-immune islet susceptibility factors may contribute to the propensity of NOD mice to develop T1D and the NODk mice to develop T2D. These results are also consistent with the beta-cell overwork hypothesis in diabetes pathogenesis as seen in NODk mice. In addition, these results show that beta-cell underwork or “lazy” beta- cells in B10k mice may protect them from more severe failure. Show more