An examination of the development of rapid onset diabetes induced by elevated exogenous glucocorticoids and a high-fat diet in young Sprague-Dawley rats

Acute increases in glucocorticoids (GCs) during a perceived stressful event are functionally important for many biological processes that include energy homeostasis. Perpetual hypothalamic-pituitary-adrenal (HP.A) axis activity continually elevates GC secretion and may induce many metabolic complications, such as peripheral insulin resistance, ectopic fat accumulation, hyperglycemia, and dyslipidemia that can increase risks of developing type 2 diabetes mellitus (T2DM). The progression into T2DM remains complex and many controversies hav1e yet to be resolved. In particular, the effect of GCs on pancreatic islet function remains relatively understudied. Therefore, we set out to develop a novel rodent model ofT2DM in young male Sprague-Dawley rats. First, we demonstrated that 2 weeks of elevated GCs and HFD induced rapid-onset diabetes (ROD), which included the following symptoms: body weight loss, hepatic steatosis, increased glucose intolerance, insulin resistance, and ectopic fat accumulation. Next, we further examined the effects of ROD on pancreatic islet function and found that ROD animals had increased β-and α-cell mass, but impaired β-cell glucose responsiveness, resulting in hyperglycemia. Regular exercise restores alterations in HPA activity and helps to protect against GC-induced hyperglycemia. This led us to investigate if regular exercise in our ROD model would help to protect against T2DM development. We found that volitional exercise was sufficient to attenuate symptoms of ROD, however not all symptoms were successfully restored, i.e. normalized glucose control and peripheral insulin resistance. We next investigated if pharmacologic agents would be able to fully reverse ROD. We demonstrated that non-selective GC receptor (GRII) antagonist fully normalized our ROD phenotype, whereas selective GRII antagonists only partially attenuated some of the ROD symptoms. Collectively, these studies take an integrative approach to T2DM development induced by GCs and HFD. We developed a model that mimics symptoms ofT2DM and concluded that GCs and HFD synergistically, not independently act to induce severe insulin resistance that burdens islet adaptive capacity. Regular exercise and pharmacological interventions were sufficient to attenuate ROD development and these therapies may be useful techniques to individuals suffering from HPA axis hyperactivity and dyslipidemia.