The dysregulation of the hypothalamic\u2013pituitary\u2013adrenal axis in diet-induced prediabetic male Sprague Dawley rats

Palesa Mosili,Bongeka Cassandra Mkhize,Ntethelelo Sibiya,Andile Khathi,Phikelelani Ngubane

doi:10.1186/s12986-020-00532-1

Palesa Mosili, Bongeka Cassandra Mkhize + Show 3 more

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https://doi.org/10.1186/s12986-020-00532-1

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Abstract

BackgroundAltered 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.MethodsSprague Dawley Rats were randomly divided into non-pre-diabetic 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 were performed in the 12-week experimental week. At the end of 32 weeks glucocorticoid and mineralocorticoid hippocampal receptors were also measured.ResultsImpaired glucose handling in the PD group as well as increase in corticosterone 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 using 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.ConclusionThese observations, together, suggest that diet-induced pre-diabetes is associated with impaired HPA axis activity and deteriorating response to stress.

Highlights

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
homeostasis model assessment (HOMA)‐IR, HOMA‐S and HOMA‐β indices, plasma adrenocorticotrophic hormone (ACTH) and corticosterone At the end of 20 weeks, glucose handling by assessing insulin sensitivity and beta-function cell through the HOMA-IR, HOMA-S and HOMA-β indices were measured along with plasma adrenocorticotropic hormone (ACTH) and corticosterone concentration
HOMA-S percentage of the pre-diabetic group (PD) was significantly lower than the non-pre-diabetic group (NPD) group while the HOMA-β percentage of the PD group was significantly higher in comparison to the NPD group

Summary

Introduction

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. Pre-diabetes is defined as an intermediary state of hyperglycaemia that occurs between normoglycaemia and type 2 diabetes mellitus (T2DM) with blood glucose concentrations above normal but below the threshold for diagnosis of diabetes [1, 2]. While T2DM is often associated with macro-and microvascular complications, studies indicate that poor management of everyday stress in diabetic patients is associated with increased risk of depression and anxiety [5,6,7]. This is said to be due to the constant activation of the hypothalamic–pituitary–adrenal (HPA) axis observed in type 2 diabetic patients [8]

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