Kisspeptin signalling and its correlation with placental ultrastructure and clinical outcomes in pregnant South African women with obesity and gestational diabetes.

INTRODUCTION: Gestational diabetes mellitus (GDM) is a major pregnancy metabolic disorder and is strongly linked with obesity. Kisspeptin is a hormone that increases several thousand-fold in the maternal circulation during human pregnancy, with placenta as its main source. Studies have suggested that kisspeptin regulates trophoblast invasion and promotes pancreatic insulin secretion and peripheral insulin sensitivity. METHODS: In a well-characterized cohort of pregnant South African women and molecular and histological techniques, this study explored the impact and interaction of maternal obesity and GDM on kisspeptin (KISS1) signalling in relation to placental morphology and maternal and neonatal parameters. RESULTS: We found that GDM had no effect on placental KISS1 and KISS1R (KISS1 receptor) mRNA and/or protein expression. However, obesity reduced placental KISS1R mRNA expression even though overall KISS1 protein abundance or localization was not different from the non-obese group. Maternal and cord circulating KISS1 concentrations did not vary with obesity or GDM, but maternal circulating KISS1 was positively correlated with placenta weight in non-GDM obese women, and negatively correlated with placental intervillous space volume in non-GDM non-obese women. Cord serum KISS1 was positively correlated with infant weight in GDM obese women, but negatively correlated with maternal BMI in the non-obese GDM group. Placental syncytiotrophoblast extracellular vesicles exhibited detectable KISS1 and its abundance was ∼50 % lower in those from obese GDM compared to non-GDM women. DISCUSSION: This study shows maternal obesity and GDM can modulate placental kisspeptin signalling and placental morphological development with potential pathophysiological implications for clinically-relevant pregnancy and perinatal outcomes.

Obesity and gestational diabetes independently and collectively induce specific effects on placental structure, inflammation and endocrine function in a cohort of South African women.

Maternal obesity and gestational diabetes mellitus (GDM) are associated with insulin resistance and health risks for mother and offspring. Obesity is also characterized by low-grade inflammation, which in turn, impacts insulin sensitivity. The placenta secretes inflammatory cytokines and hormones that influence maternal glucose and insulin handling. However, little is known about the effect of maternal obesity, GDM and their interaction, on placental morphology, hormones and inflammatory cytokines. In a South African cohort of non-obese and obese pregnant women with and without GDM, this study examined placental morphology using stereology, placental hormone and cytokine expression using real-time PCR, western blotting and immunohistochemistry, and circulating TNFα and IL-6 concentrations using ELISA. Placental expression of endocrine and growth factor genes was not altered by obesity or GDM. However, LEPTIN gene expression was diminished, syncytiotrophoblast TNFα immunostaining elevated and stromal and fetal vessel IL-6 staining reduced in the placenta of obese women in a manner that was partly influenced by GDM status. Placental TNFα protein abundance and maternal circulating TNFα concentrations were reduced in GDM. Both maternal obesity and, to a lesser extent, GDM were accompanied by specific changes in placental morphometry. Maternal blood pressure and weight gain and infant ponderal index were also modified by obesity and/or GDM. Thus, obesity and GDM have specific impacts on placental morphology and endocrine and inflammatory states that may relate to pregnancy outcomes. These findings may contribute to developing placenta-targeted treatments that improve mother and offspring outcomes, which is particularly relevant given increasing rates of obesity and GDM worldwide. KEY POINTS: Rates of maternal obesity and gestational diabetes (GDM) are increasing worldwide, including in low-middle income countries (LMIC). Despite this, much of the work in the field is conducted in higher-income countries. In a well-characterised cohort of South African women, this study shows that obesity and GDM have specific impacts on placental structure, hormone production and inflammatory profile. Moreover, such placental changes were associated with pregnancy and neonatal outcomes in women who were obese and/or with GDM. The identification of specific changes in the placenta may help in the design of diagnostic and therapeutic approaches to improve pregnancy and neonatal outcomes with particular significant benefit in LMICs.

Integrated Management of Type 2 Diabetes and Gestational Diabetes in the Context of Multi-Morbidity in Africa: A Systematic Review.

Introduction: Many adults diagnosed with gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (T2DM) also have other known or unknown comorbid conditions. The rising prevalence of GDM and T2DM within a broader context of multimorbidity can best be addressed through an integrated management response, instead of stand-alone programs targeting specific infectious and/or chronic diseases. Aim: To describe GDM and T2DM screening, care and cost-effectiveness outcomes in the context of multimorbidity through integrated interventions in Africa. Methods: A systematic review of all published studies was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Risk Of Bias in Non-randomised Studies of Interventions (ROBINS-I) was used to assess risk of bias. Data synthesis was conducted using narrative synthesis of included studies. Results: A total of 9 out of 13 included studies reported integrated diabetes mellitus (DM) screening, 7 included integrated care and 9 studies addressed cases of newly detected DM who were asymptomatic in pre-diabetes stage. Only 1 study clearly analysed cost-effectiveness in home-based care; another 5 did not evaluate cost-effectiveness but discussed potential cost benefits of an integrated approach to DM screening and care. Compared to partial integration, only 2 fully integrated interventions yielded tangible results regarding DM screening, care and early detection of cases despite many that reported barriers to its sustainability. Conclusion: Though few, integrated interventions for screening and/or care of DM in the context of multimorbidity within available resources in health systems throughout Africa exist and suggest that this approach is possible and could improve health outcomes.

Kisspeptins and Glucose Homeostasis in Pregnancy: Implications for Gestational Diabetes Mellitus-a Review Article.

Gestational diabetes mellitus (GDM) is becoming an increasingly common complication of pregnancy with the global rise of obesity. The precise pathophysiological mechanisms underpinning GDM are yet to be fully elucidated. Kisspeptin, a peptide encoded by the KISS1 gene, is mainly expressed by placental syncytiotrophoblasts during pregnancy. It is an essential ligand for kisspeptin 1 receptor (KISS1R), which is expressed by both the villous and invasive extravillous cytotrophoblast cells. Circulatory kisspeptins rise dramatically in the second and third trimester of pregnancy coinciding with the period of peak insulin resistance. Kisspeptins stimulate glucose-dependent insulin secretion and decreased plasma levels inversely correlate with markers of insulin resistance. Additionally, kisspeptins play a critical role in the regulation of appetite, energy utilisation and glucose homeostasis. GDM pregnancies have been associated with low circulatory kisspeptins, despite higher placental kisspeptin and KISS1R expression. This review evaluates the role of kisspeptin in insulin secretion, resistance and regulation of appetite as well as its implications in GDM.

Implementation and impact of mobile health (mHealth) in the management of diabetes mellitus in Africa: a systematic review protocol.

INTRODUCTION: The WHO has proposed the concept of mobile health (mHealth) to support healthcare systems delivery worldwide. mHealth basically involves the use of Information and Communication Technology for healthcare provision or delivery services. Africa has seen a remarkable increase in mobile phone availability and usage in the last decade. The incidence and prevalence of diabetes mellitus (DM) in Africa have also been on the increase in the last decade, in sharp contrast to an ailing healthcare system. We aim to review the extent of implementation of mHealth in the management of DM in Africa, and estimate its impact in helping patients achieve desired glycaemic target, sustain control and prevent complications in the past decade. METHODS AND ANALYSIS: Studies assessing the utilisation of mhealth in the management of patients with DM in Africa will be considered based on the PICO method: Population, Intervention, Comparator, and Outcomes. Medline, PubMed, SCOPUS and the Pan African Clinical Trials Registry, among others will be searched. Two authors independent of each other shall screen titles and abstracts retrieved using the search strategy, retrieve the full text articles and assess them for eligibility and extract data. A third reviewing author will be brought in to resolve any disagreement between the two authors by discussion. The 'Cochrane Collaboration Risk of Bias Tool' will be used to assess the quality of included studies. A narrative synthesis of extracted data and, where the characteristics of the eligible studies permit, a meta-analysis (which will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines) will be done. ETHICS AND DISSEMINATION: No ethical approval will be required since only published data will be used. Dissemination of results will be through peer reviewed publication and conference presentation. PROSPERO REGISTRATION NUMBER: CRD42021218674.

Clinical and biochemical correlates of hypogonadism in men with type 2 diabetes mellitus.

INTRODUCTION: there is an association between hypogonadism and obesity, chronic hyperglycaemia, and ageing in men with type 2 diabetes mellitus (T2DM). T2DM is known to be associated with low testosterone. There is a paucity of data on the risk factors of hypogonadism in Nigerian men with T2DM. The objective of this study was to determine the clinical and biochemical correlates of hypogonadism and clinical predictors of low total testosterone levels in men with T2DM. METHODS: this was a cross-sectional study consisting of 358 men with T2DM and 179 non-diabetic men (controls). Structured Androgen Deficiency in the Ageing Male questionnaire was administered. Clinical and biochemical parameters were measured. Free testosterone was calculated from albumin, SHBG and total testosterone using Vermeulen´s method. Hypogonadism was defined as fasting TT as < 8 nmol/L with or without symptoms or TT of 8-12 nmol/L with symptoms of androgen deficiency. Low testosterone was defined as serum total testosterone levels ≤ 12 nmol/L. RESULTS: the mean (±SD) total testosterone of men with T2DM and controls were 8.79±3.35 nmol/L and 15.41±3.79 nmol/L respectively (p < 0.001). The risk of hypogonadism was associated with central obesity (Odds ratio [OR] 2.24, 95% confidence interval [CI] 0.38-13.07), systolic hypertension (OR 3.93, 95% CI 0.67-23.10), hyperglycaemia (OR 2.48, 95% CI 0.37-16.46) and hypercholesterolaemia (OR 2.50, 95% CI 0.43-14.61). In a multivariable regression analysis, there was a significant negative correlation between total testosterone and triglycerides (r -1.85, 95% CI -3.58 - 0.12, P = 0.04) and HDL cholesterol (r -1.25, 95% CI -5.95-3.45, P = 0.02). CONCLUSION: this study shows that in men with T2DM, triglycerides and HDL cholesterol are independent correlates of hypogonadism but not central adiposity, systolic blood pressure and glycaemia. Further large prospective studies are recommended.

Outcomes of hyperglycaemia in pregnancy in Africa: systematic review study protocol.

INTRODUCTION: The prevalence of diabetes mellitus globally has increased considerably over the past decades with a resultant increase in the incidence of diabetes-complicated pregnancies. Hyperglycaemia in pregnancy is the most common metabolic complication encountered during pregnancy and is associated with adverse maternal and fetal outcomes. This systematic review aims to examine maternal, fetal, neonatal, childhood and long-term maternal outcomes of hyperglycaemia in pregnancy in Africa. METHODS AND ANALYSIS: A systematic review of all studies that investigated hyperglycaemia in pregnancy outcomes, carried out in Africa from 1998 to 2019. A comprehensive search of all published articles indexed in PubMed-MEDLINE, Cochrane Library, Scopus, CINAHL (EBSCOhost), Embase and Web of Science databases will be performed. Studies will be screened for eligibility by title, abstract and full text in duplicate by two independent reviewers. For data where meta-analysis is not possible, narrative analysis will be carried out using themes from data. For data where meta-analysis is possible, random effects meta-analysis will be conducted. This systematic review will be reported according to the Meta-analyses of Observational Studies in Epidemiology. ETHICS AND DISSEMINATION: Ethical approval is not required for this study considering this is a systematic review protocol that uses only published data. The findings of this study will be disseminated through peer-reviewed publications and conference presentations. PROSPERO REGISTRATION NUMBER: CRD42020184573.

Integrated management of type 2 diabetes and gestational diabetes within multi-morbidity conditions in Africa: a systematic review protocol.

INTRODUCTION: Multi-morbidity, defined as the co-existence of more than one chronic condition in one person, has been increasing due to comorbid non-communicable and infectious chronic diseases (CNCICDs). Type 2 diabetes (T2D) and gestational diabetes mellitus (GDM) incidences within the CNCICDs conditions are increasing and overwhelming already weak and under-resourced healthcare systems in Africa. There is then an urgent need for the integrated management of CNCICDs. We aim to review the integrated management of T2D and GDM within multi-morbidity conditions in Africa. METHODS: Studies that have assessed the integrated management of T2D and GDM within multi-morbidity conditions in Africa will be considered based on the Population, Intervention, Comparator and Outcome method: population (adult diagnosed with T2D and GDM, who also have other diseases, non-communicable diseases (NCDs) and infectious, in public primary and secondary healthcare facilities in Africa); Intervention (integrated management of T2D and GDM, also suffering from other diseases in Africa), Comparator (Unintegrated management of T2D and GDM in Africa) and Outcomes (integrated management of T2D and GDM in Africa). The following databases Cochrane Library, MEDLINE, PubMed and SCOPUS, the WHO International Clinical Trials Registry Platform, among others will be searched. Two reviewers (JCM and MW) will independently screen, select eligible studies and extract data. Discrepancies will be resolved by consensus or by a discussion with the third author (AR). Quality of included studies will be assessed using both the newly developed tool, 'the Cochrane Collaboration Risk of Bias Tool' and 'Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I)". A narrative synthesis of extracted data and meta-analysis, if necessary will be conducted and then reported according to the preferred reporting items for systematic review and meta-analysis. ETHICS CONSIDERATION AND DISSEMINATION: By only using the published data, there is no ethics approval required for this study. This systematic review will be included in JCM's PhD thesis and its findings will also be disseminated through peer-reviewed publication and conference presentation. PROSPERO REGISTRATION NUMBER: CRD42016046630.