High glucocorticoids, in combination with high‐fat feeding, induces insulin resistance and hyperglycaemia: Mechanisms related to beta cell dysfunction?

Glucocorticoids (GCs) are known to increase insulin resistance and β cell mass. High‐fat feeding induces insulin resistance but causes β cell death. Rarely has GCs and high‐fat feeding together been investigated on β cell function. We hypothesize that the addition of high‐fat feeding to GC therapy will result in β cell exhaustion and hyperglycaemia. We examined the short‐term effect of these stressors on β cell dynamics in male Sprague‐Dawley rats (age ~6 wks). Rats were given corticosterone pellets (CORT) (400mg/rat) or wax pellets (controls) with or without high‐fat feeding (HF) (n=5–6 per group). After 5 days of treatment, fed blood glucose levels in CORT‐HF rats only were found to be elevated (>11 mM), while fasted insulin concentrations were 5‐fold higher vs. controls (P<0.05). Insulin positive staining indicated β cell mass in CORT and CORT‐HF treated animals to be 1.5 fold higher compared to controls (p<0.05). Mean islet areas and β cell number per islet were found to be increased by 1.5 and 1.9 fold, respectively, in CORT/CORT‐HF vs. controls (both p<0.05). Interestingly, β cell size was smaller in these animals (by 23 %) compared to controls. There was no evidence of β cell neogenesis as measured by ductal growth. We conclude that CORT and high‐fat feeding act synergistically to exhaust normal β cell function, thereby resulting in accelerated T2DM development. This project was funded by CDA and NSERC.