The relationship between adipose tissue RAAS activity and the risk factors of prediabetes in different ethnicities: A protocol for a systematic review and meta-analysis.

BACKGROUND: The incidence and prevalence of prediabetes has become a global concern. The risk factors of prediabetes, such as insulin resistance, adiposity, lipotoxicity and obesity, in conjunction with the alteration of the renin-angiotensin-aldosterone system (RAAS), have been positively correlated with the high morbidity and mortality rate. Thus, this systematic review seeks to establish the relationship between the risk factors of prediabetes, namely insulin resistance adiposity, lipotoxicity, obesity and the RAAS. Therefore, a synthesis of these risk factors, their clinical indicators and the RAAS components will be compiled in order to establish the association between the RAAS alteration and obesity in prediabetic patients. METHODS: This protocol for a systematic review was developed in compliance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) standards. This will be accomplished by searching clinical Medical Subject Headings categories in MEDLINE with full texts, EMBASE, Web of Science, PubMed, Cochrane Library, Academic Search Complete, ICTRP and ClinicalTrial.gov. Reviewers will examine all of the findings and select the studies that meet the qualifying criteria. To check for bias, the Downs and Black Checklist will be used, followed by a Review Manager v5. A Forrest plot will be used for the meta-analysis and sensitivity analysis. Furthermore, the strength of the evidence will be assessed utilizing the Grading of Recommendations Assessment, Development, and Evaluation procedure (GRADE). The protocol has been registered with PROSPERO CRD42022320252. This systematic review and meta-analysis will include published randomized clinical trials, observational studies and case-control studies from the years 2000 to 2022.

Review of the direct and indirect effects of hyperglycemia on the HPA axis in T2DM and the co-occurrence of depression.

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.