The Dysregulation of the Hypothalamic-pituitary-adrenal Axis in Diet-induced Prediabetic Male Sprague Dawley Rats

Abstract

Background: Altered function of the hypothalamic-pituitary-adrenal (HPA) axis in type 2 diabetic patients, a condition preceded by pre-diabetes, has been shown to increase the risk of depression as well as cause downstream effects resulting in upregulation of gluconeogenesis and dyslipidemia. In addition, stress, either psychological from managing diabetes or lifestyle related, further activates the HPA axis causing an exaggerated stress response. This study investigated the activity of the HPA axis in selected markers of glucose handling, and the stress response relative to components of the HPA axis in a diet-induced pre-diabetic rat model. Methods: Sprague Dawley Rats were randomly divided into non-prediabetic group (NPD) and pre-diabetic group (PD) (n=6, per group) over a 20-week induction period and a further 12-week experimental period to get 32 weeks. At the end of the 20 and 32-week periods, insulin resistance using the HOMA-IR index, adrenocorticotropic (ACTH) and corticosterone (CORT) concentrations were measured. Stress was induced and the forced swim test (FST) were performed in the 12-week experimental week. At the end of 32 weeks glucocorticoid and mineralocorticoid hippocampal receptors were measured too. Results: Impaired glucose handling in the PD group as well as increase in corticosterone (CORT) was observed at the end of both 20 and 32-week periods by comparison to NPD groups. No changes were observed in ACTH concentration at week 20 while, at week 32, a decrease in plasma ACTH concentration was observed in the PD group by comparison to the NPD group. The stressed-induced animals were stressed underwent the forced swim test: the behaviour observed showed an increase in immobility time in the PD stressed group by comparison to the NPD group. This was followed by the observation of a decrease in ACTH and CORT concentration in the PD stressed group by comparison to the NPD stressed group. Mineralocorticoid and glucocorticoid receptors gene expression were elevated in the stressed PD group relative to the stressed NPD group. Conclusion: These observations, together, suggest that diet-induced pre-diabetes is associated with impaired HPA axis activity and deteriorating response to stress.

The ‘Jekyll and Hyde’ of Gluconeogenesis: Early-Life Adversity, Later Life Stress, and Metabolic Disturbances

“…Furthermore, when Mosili et al induced a chronic stress together with pre-diabetes, the rats were unable to mount a normal ACTH or GC response to subsequent acute stressor. further consolidating their observation of either impaired GC signalling or negative feedback [67]. Interestingly, diet would appear to affect the adrenal gland as increased GC secretion, adrenal cortical hyperplasia, and increased steroidogenesis have been reported in T2D-and obesity-inducing high fat diets [69].…”

“…Mechanistically, this passes through altered secretion of ACTH from the pituitary gland, leading to altered GC levels [65,66]. In a series of particularly well designed experiments, Mosili et al demonstrated that as rats entered a prolonged pre-diabetic state baseline ACTH levels under non-stressful conditions dropped, but GC levels were significantly elevated [67]. The HPA axis negative feedback loop should, under normal conditions bring down GC levels when ACTH levels are low [68] suggesting that the negative feedback is somehow impaired [65].…”