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, glucose handling using the Homeostasis Model Assessment indices, 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.

Dietary intervention in depression – a review

“…An excessive fructose intake crosses the blood-brain barrier (BBB) through glucose transporter 5 and accumulates in the hypothalamus. 25 This leads to excessive activation of the HPA axis and increased cortisol secretion, which increases the risk of depression. 25 In a double-blind, randomized and placebo-controlled clinical trial, compared with the placebo group, urinary cortisol levels in the prebiotic and probiotic groups decreased by 19% and 20%, respectively.…”

“…25 This leads to excessive activation of the HPA axis and increased cortisol secretion, which increases the risk of depression. 25 In a double-blind, randomized and placebo-controlled clinical trial, compared with the placebo group, urinary cortisol levels in the prebiotic and probiotic groups decreased by 19% and 20%, respectively. 26 Furthermore, panaxynol can inhibit the dysregulation of the HPA axis by inhibiting the content of the CRH in the hypothalamus and increasing the expression of the GR.…”

Stress Induced Cortisol Release Depresses The Secretion of Testosterone in Patients With Type 2 Diabetes Mellitus

“… 13 Patients with diabetes have increased HPA axis activation. 14 According to, 15 there might be a link between stress, diabetes, and plasma cortisol levels. Cortisol and testosterone levels in T2DM patients and controls were to be compared as part of this investigation.…”

Assessing the risk factors for myocardial infarction in diet-induced prediabetes: myocardial tissue changes

“…Studies have demonstrated that T2DM related complications begin during prediabetes [23,24]. Studies in our laboratory using the high-fat-high-carbohydrate (HFHC) diet-induced model of prediabetes have demonstrated that kidney and brain injury occurs during prediabetes [25,26]. However, any injury to the myocardium during prediabetes have not been investigated.…”