Exogenous Glucocorticoids and a High-Fat Diet Cause Severe Hyperglycemia and Hyperinsulinemia and Limit Islet Glucose Responsiveness in Young Male Sprague-Dawley Rats

Corticosterone (CORT) and other glucocorticoids cause peripheral insulin resistance and compensatory increases in beta-cell mass. A prolonged high-fat diet (HFD) induces insulin resistance and impairs beta-cell insulin secretion. This study examined islet adaptive capacity in rats treated with CORT and a HFD. Male Sprague-Dawley rats (age similar to 6 weeks) were given exogenous CORT (400 mg/rat) or wax (placebo) implants and placed on a HFD (60% calories from fat) or standard diet (SD) for 2 weeks (N = 10 per group). CORT-HFD rats developed fasting hyperglycemia (>11 mM) and hyperinsulinemia (similar to 5-fold higher than controls) and were 15-fold more insulin resistant than placebo-SD rats by the end of similar to 2 weeks (Homeostatic Model Assessment for Insulin Resistance [HOMA-IR] levels, 15.08 +/- 1.64 vs 1.0 +/- 0.12, P < .05). Pancreatic beta-cell function, as measured by HOMA-beta, was lower in the CORT-HFD group as compared to the CORT-SD group (1.64 +/- 0.22 vs 3.72 +/- 0.64, P < .001) as well as acute insulin response (0.25 +/- 0.22 vs 1.68 +/- 0.41, P < .05). Moreover, beta- and alpha-cell mass were 2.6- and 1.6-fold higher, respectively, in CORT-HFD animals compared to controls (both P < .05). CORT treatment increased p-protein kinase C-alpha content in SD but not HFD-fed rats, suggesting that a HFD may lower insulin secretory capacity via impaired glucose sensing. Isolated islets from CORT-HFD animals secreted more insulin in both low and high glucose conditions; however, total insulin content was relatively depleted after glucose challenge. Thus, CORT and HFD, synergistically not independently, act to promote severe insulin resistance, which overwhelms islet adaptive capacity, thereby resulting in overt hyperglycemia.