Introduction: NODk mice, derived from the non-obese diabetic (NOD) mouse, are type 1 diabetes resistant, but develop marked hyperinsulinaemia followed by a severe type 2 diabetes phenotype when fed >10 weeks on a high fat (HF) diet. We hypothesized that islet b-cell hyper-responsiveness of the NODk mouse underpins its diabetes susceptibility.
Objectives: To determine the effects of a 5-day HF diet challenge (HFDC) on insulin secretion in the NODk mouse and two-comparator stains, C57Bl10 (B10) and Balb/c.
Methods: The effects of the 5-day HFDC compared to remaining on chow diet on male NODk, B10 and Balb/c mice at 8 weeks of age were studied. Morning body weight (BW), fed-state blood glucose and plasma insulin were measured on day-0 and day-5. An intra-peritoneal glucose tolerance test (ipGTT) with plasma insulin measurements was performed on day 5 after a 6h fast. Insulin responsiveness was assessed by analysis of the ipGTT ratio of the insulin area under the curve (AUC), to the glucose AUC (insAUC/glucAUC).
Results: The HFDC increased BW in NODk and Balb/c mice only. Fed-state and ipGTT glycaemia was best in chow-fed NODk mice (fed-glucose (mM); 6.4±0.1, 7.6±0.2, 7.5±0.2; ANOVA p<0.001; NODk, B10, Balb/c). The 5-day HFDC had little effect on glucose levels within strains. The HFDC, however, caused marked hyperinsulinaemia in NODk mice only (fed-insulin (ng/mL); 3.8±0.6, 0.5±0.08, 0.8±0.13; p<0.001). The insAUC/glucAUC showed much greater insulin responsiveness in NODk compared to the B10 and Balbc strains on both chow diet (ng/ml:mM); 0.14±0.01, 0.03±0.1, 0.06±0.01; p<0.001) and after the 5 day HFDC (0.31±0.06, 0.04±0.01, 0.08±0.01; p<0.001).
Conclusions: The results support the hypothesis that NODk mice have hyper-responsive b-cells that is evident even on chow-diet. This hyper-responsiveness may drive excessive weight gain and later b-cell failure in NODK mice. The converse of insulin hypo-responsiveness was seen in diabetes resistant B10 mice.