Type 2 diabetes mellitus (T2DM) is characterized by persistent hyperglycemia which is further associated with hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. Several studies have shown that HPA axis hyperactivity is heightened in the chronic hyperglycemic state with severe hyperglycemic events more likely to result in a depressive disorder. The HPA axis is also regulated by the immune system. Upon stress, under homeostatic conditions, the immune system is activated via the sympatho-adrenal-medullary axis resulting in an immune response which secretes proinflammatory cytokines. These cytokines aid in the activation of the HPA axis during stress. However, in T2DM, where there is persistent hyperglycemia, the immune system is dysregulated resulting in the elevated concentrations of these cytokines. The HPA axis, already activated by the hyperglycemia, is further activated by the cytokines which all contribute to a diagnosis of depression in patients with T2DM. However, the onset of T2DM is often preceded by pre-diabetes, a reversible state of moderate hyperglycemia and insulin resistance. Complications often seen in T2DM have been reported to begin in the pre-diabetic state. While the current management strategies have been shown to ameliorate the moderate hyperglycemic state and decrease the risk of developing T2DM, research is necessary for clinical studies to profile these direct effects of moderate hyperglycemia in pre-diabetes on the HPA axis and the indirect effects moderate hyperglycemia may have on the HPA axis by investigating the components of the immune system that play a role in regulating this pathway.

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-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. Results: Impaired 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. Conclusion: These observations, together, suggest that diet-induced pre-diabetes is associated with impaired HPA axis activity and deteriorating response to stress.

Type 2 diabetes (T2D) is associated with a plethora of comorbidities, including osteoporosis, which occurs due to an imbalance between bone resorption and formation. Numerous mechanisms have been explored to understand this association, including the renin–angiotensin–aldosterone system (RAAS). An upregulated RAAS has been positively correlated with T2D and estrogen deficiency in comorbidities such as osteoporosis in humans and experimental studies. Therefore, research has focused on these associations in order to find ways to improve glucose handling, osteoporosis and the downstream effects of estrogen deficiency. Upregulation of RAAS may alter the bone microenvironment by altering the bone marrow inflammatory status by shifting the osteoprotegerin (OPG)/nuclear factor kappa-Β ligand (RANKL) ratio. The angiotensin-converting-enzyme/angiotensin II/Angiotensin II type 1 receptor (ACE/Ang II/AT1R) has been evidenced to promote osteoclastogenesis and decrease osteoblast formation and differentiation. ACE/Ang II/AT1R inhibits the wingless-related integration site (Wnt)/β-catenin pathway, which is integral in bone formation. While a lot of literature exists on the effects of RAAS and osteoporosis on T2D, the work is yet to be consolidated. Therefore, this review looks at RAAS activity in relation to osteoporosis and T2D. This review also highlights the relationship between RAAS activity, osteoporosis and estrogen deficiency in T2D.

A dysregulated hypothalamic–pituitary–adrenal (HPA) axis in patients with type 2 diabetes (T2D), a condition preceded by prediabetes, has been shown to exacerbate the hyperglycaemic state, increasing the risk of depression. However, HPA axis activity in a prediabetic state—as well as whether the prediabetic state affects HPA axis regulation—is not fully understood. This study investigated the activity of the HPA axis in selected biomarkers and hormones related to HPA axis regulation in individuals with prediabetes. The study used samples obtained from adults aged between 25 and 45 of all ethnicities from the King Edward VIII Hospital. The samples were divided into three groups—non-prediabetic (NPD) (n = 40), prediabetic (PD) (n = 40), and T2D (n = 40)—based on the participant’s glycated haemoglobin percentage. The cortisol (CORT), adrenocorticotropic hormone (ACTH), insulin, epinephrine (EPI), and norepinephrine (NE) concentrations of the samples were measured. The plasma CORT and ACTH concentrations in the PD group were higher compared to the NPD group. Plasma insulin concentration was increased only in the T2D group. There was also an increase in the plasma epinephrine concentration in the T2D group as compared to the NPD and PD groups. These observations collectively suggest that prediabetes is associated with heightened HPA axis activity and may alter HPA axis regulation, which may cause an altered stress response.

Adipose tissue is essential for the regulation of insulin sensitivity and cytokine production, which are key processes in maintaining metabolic homeostasis. Previous studies have shown a link between the renin–angiotensin system (RAS) and adipose tissue dysfunction in type 2 diabetes (T2D); however, the role of RAS in prediabetes remains underexplored. This study aimed to analyze the association between RAS components and adipose tissue dysfunction in the prediabetic state. This observational, cross-sectional study was conducted between 21/05/21 and 20/05/24 and analyzed RAS markers in plasma samples. This study was conducted at King Edward Hospital, focusing on individuals from outpatient clinics. The study included non-prediabetic (NPD), prediabetic (PD), and T2D individuals (n = 40 per group) aged 25–45 years. The participants were selected based on fasting blood glucose levels and HbA1c criteria. Plasma RAS markers and adipose function markers were measured in each participant. Primary outcomes included HOMA-IR, HbA1c, and plasma levels of ACE1, Ang II, ACE2, Ang 1-7, adiponectin, adipsin, MCP-1, and HDL. PD participants had significantly altered glycaemic control (HOMA-IR: 2.1 ± 0.4 vs. 3.9 ± 0.8; HbA1c: 4.9 ± 0.4 vs. 5.9 ± 0.6) compared to NPD. Plasma ACE1 (162.0 ± 10.55 vs. 180.3 ± 7.546) and Ang II (20.26 ± 2.404 vs. 25 ± 1.752) were elevated, while adiponectin (29.08 ± 5.72 vs. 23.22 ± 4.93) and HDL (1.01 ± 0.11 vs. 0.67 ± 0.11) were reduced in PD. Alterations in RAS manifest early in prediabetes and are associated with adipose tissue dysfunction. These findings suggest that RAS dysregulation contributes to early metabolic disturbances in prediabetes.

There is a correlation between the existence of type 2 diabetes mellitus (T2DM) and the development of thyroid disorders. Prediabetes is a progressive state of moderate insulin resistance that often precedes the onset of T2DM. However, the association between prediabetes and thyroid function is unknown. This study assessed changes in markers of thyroid function in diet-induced prediabetes. Twelve male Sprague Dawley rats (n = 12) were randomly assigned into two groups. Rats in the non-prediabetic (NPD) group were fed a standard rat diet, while rats in the prediabetic (PD) were fed a high-fat high-carbohydrate diet for 20 weeks to induce prediabetes. Thereafter, fasting blood glucose levels were measured. Plasma samples were assessed for triiodothyronine (T3), thyroxine (T4), thyroxine peroxidase (TPO) antibody, insulin, and glycated hemoglobin (HbA1c) concentrations. The elevated blood glucose, HbA1c, and plasma insulin levels coincided with increased T3 and reduced T4 levels in the PD group when compared to the NPD group. There was also an increase in the concentration of TPO antibodies in the PD group. Additionally, there was a significant correlation between the thyroid hormone concentrations and HbA1c levels. In conclusion, these results indicated that there is a positive association between thyroid dysfunction and diet-induced prediabetes in rats.