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.

Aims/Introduction: Derangements often observed with type 2 diabetes are associated with disturbances in renin–angiotensin–aldosterone system (RAAS) activity. A positive correlation between local RAAS activity and the complications observed in type 2 diabetes has been noted. However, the detrimental ramifications due to moderate hyperglycemia noted in prediabetes, and the affected organ system and mechanistic pathways are not elucidated. Hence, this study investigated the effects of diet‐induced prediabetes on RAAS in various organs.Materials and Methods: Male Sprague–Dawley rats were separated into two groups: (i) non‐prediabetes through exposure to standard rat chow group; and (ii) diet‐induced prediabetes group by exposure to a high‐fat high‐carbohydrate diet for 32 weeks. RAAS activity in the skeletal muscle, adipose tissue, liver, pancreas and heart was determined through the analysis of RAAS components, such as renin, angiotensinogen, angiotensin‐converting enzyme and angiotensin II type 1 receptor through polymerase chain reaction, as well as the quantification of angiotensin II and aldosterone concentration. Furthermore, nicotinamide adenine dinucleotide phosphate oxidase, superoxide dismutase and glutathione peroxidase 1 concentrations were determined in the skeletal muscle, pancreas and heart, in addition to the hepatic triglycerides.Results: The RAAS components were elevated in the diet‐induced prediabetes group when compared with the non‐prediabetes group. This was further accompanied by increased nicotinamide adenine dinucleotide phosphate oxidase and reduced superoxide dismutase and glutathione peroxidase 1 concentrations in the selected organs, in addition to the elevated hepatic triglycerides concentration in the diet‐induced prediabetes by comparison to non‐prediabetes group.Conclusions: Due to these observed changes, we suggest that local RAAS activity in the prediabetes state in selected organs elicits the derangements noted in type 2 diabetes.

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.

This systematic review was developed in compliance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-2020) standards. This was accomplished by searching clinical MeSH categories in MEDLINE with full texts, EMBASE, Web of Science, PubMed, Cochrane Library, Academic Search Complete, ICTRP and ClinicalTrial.gov. Reviewers examined all the findings and selected the studies that satisfied the inclusion criteria. The Downs and Black Checklist was used to assess for bias, followed by a Review Manager v5. A Forrest plot was used for the meta-analysis and sensitivity analysis. The protocol for this review was registered with PROSPERO CRD42022320252. The clinical studies (n = 2) comprised 1065 patients with prediabetes and 1103 normal controls. The RAAS measurements were completed in the adipose tissue. The RAAS components, renin and aldosterone were higher in the prediabetic (PD) compared to the control [mean difference (MD) = 0.16, 95% CI 0.16 (-0.13, 0.45), p = 0.25]. Furthermore, the PD group demonstrated higher triglycerides mean difference [MD = 7.84, 95% CI 7.84 (-9.84, 25.51), p = 0.38] and increased BMI [MD = 0.13, 95% CI 0.13 (-0.74, 0.99), p = 0.77] compared to the control. The overall quality of the studies was fair with a median score and range of 17 (16-18). The current study highlights the relationship between increased BMI, RAAS and insulin resistance which is a predictor of prediabetes. The renin is slightly higher in the prediabetes group without any statistical significance, aldosterone is rather negatively associated with prediabetes which may be attributed to the use of anti-hypertensive treatment.

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.