4. Electronic Theses and Dissertations (ETDs) - Faculties submissions
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Item MicroRNA expression and arterial function in type II diabetes mellitus(University of the Witwatersrand, Johannesburg, 2024) Goldfein, Batsheva; Millen, AlettaBackground. Type II diabetes mellitus (T2DM) is a major health concern which significantly contributes to the global cardiovascular disease (CVD) burden. Arterial dysfunction is considered a subclinical marker of CVD and is associated with an increased risk of cardiovascular events. However, treatment outcomes for T2DM patients remain suboptimal, mainly due to a poor understanding and the lack of an early marker for the identification of subclinical CVD. Recently, microRNAs (miRNA), small, non-coding RNA molecules that regulate major signalling pathways through post-transcriptional modification, have been identified as possible epigenetic regulators in the development of many diseases. MiR-146a-5p, in particular, has received considerable attention as a biomarker associated with several disease states including inflammation, T2DM and CVD. However, studies surrounding the role of miR- 146a-5p in arterial function and subclinical CVD risk in diabetic populations have yielded contradictory results. Therefore, the aim of this study was to determine the role of miR-146a-5p expression in the development of arterial dysfunction in patients with T2DM. Methods. This case control study (n=118) included participants with a previous diagnosis of insulin resistance or T2DM (n=67), and a non-DM control group (n=51). Demographic characteristics and CVD risk factors were assessed using standard approaches. Arterial function was measured using applanation tonometry and SphygmoCor software. From the recorded radial and aortic waveforms, central systolic (cSBP) and pulse pressure (cPP), augmentation pressure (AP) and the forward (FWP) and reflected wave pressure (RWP) were derived using a generalised transfer function. The carotid-femoral pulse wave velocity (PWV) was measured as a marker of arterial stiffness. Using a fasting blood sample, serum concentrations of tumour necrosis factor α (TNFα) and matrix metalloproteinase 1 (MMP1) were quantified by ELISA. Real time quantitative PCR was used to determine the relative expression of miR-146a-5p using the comparative CT method relative to an endogenous control miRNA, miR-16-5p. Differences in anthropometric variables, miRNA expression and arterial function between the two groups were determined using unpaired t-tests or Mann Whitney U tests, as appropriate. Associations between miR-146a-5p expression and arterial function were determined using Pearson’s correlations. Participants were further stratified according to CVD risk using the Framingham risk score (FRS), and the associations with miRNA expression analysed using multivariate linear regression. Results. Participants with DM had significantly higher body mass index (p=0.002), triglyceride levels (p=0.004), and systolic blood pressure (p<0.001) than the control participants. Diabetic participants also had increased CVD risk compared to the control group, as assessed using FRS (P<0.001). Participants with DM also had significantly higher cSBP (p=0.003), mean arterial pressure (p<0.001), peripheral PP (p=0.04), FWP (p=0.045) and PWV (p=0.04). The relative expression of miR-146a-5p was significantly increased in the DM group compared to the control group (p=0.02). Across the study cohort, miR-146a-5p expression was significantly associated with waist-to- hip ratio (partial r=0.29, p = 0.002), triglyceride concentrations (partial r=0.2, p = 0.04), the atherogenic index (partial r=0.20, p=0.04) and TNFα concentrations (partial r=0.23, p=0.02), in age, sex and race adjusted analysis. In multivariate adjusted analysis, miR- 146a-5p expression was not associated with any of the arterial function variables (all p>0.05). However, when stratifying participants based on CVD risk, in those with a high risk for CVD (FRS≥20), miR-146a-5p was inversely associated with peripheral PP (Std β=-0.76, p=0.03, cPP (Std β=-0.76, p=0.01), cSBP (Std β=-0.38, p=0.02), FWP (Std β=-0.68, p=0.04) and RWP (Std β=-0.66, p=0.04). When MMP1 was included as a confounder, these associations were no longer significant. Conclusion. MiR-146a-5p expression was significantly higher in participants with T2DM compared to control participants and was significantly associated with traditional CVD risk factors and inflammation. MiR-146a-5p expression was not association with arterial function measures in the total population. Interestingly, in patients at a high risk for CVD, decreased expression of miR-146a-5p was associated with increased pressure pulsatility and wave reflection. These associations were lost when MMP1, a marker of arterial remodelling, was included as a confounding factor. These results suggest that miR-146a-5p may have a regulatory role in the development of arterial dysfunction through arterial remodelling in persons at high risk for CVD.Item A critical analysis of sugar tax in South Africa(University of the Witswatersrand, Johannesburg, 2022-03-30) Irinoye, Nakedi Jane Vanessa; Blumenthal, RoyGlobally the major leading cause of death is associated with non-communicable diseases (NCDs) and increasing in both First and Third World countries, including South Africa. The change from traditional to processed food, more energy-dense food, sugar-based drinks, more added salt, fat and sugar, are all referred to as the ‘western diet’. The transition of the food environment has been associatedwith individual influences such as behaviors, knowledge and attitudes. Globally the consumption of sugar-based drinks has increased at an alarming rate and major non-communicable diseases (NCDs) are associated with the excessive intake of sugar. One of the global health risks is obesity. In creating food environments that are healthy, international jurisdictions formulate policies and environmental interventions as an effective tool. Taxes have been employed to stabilise a downturn in the market and change the price, which have affected consumers’ purchasing decisions. In this report, sugar tax was critically analysed by evaluating the impact of the tax on the market, employment, imports and exports. Several policy design options of taxing sugar-based drinks as formulated and introduced by the World Health Organization (WHO) and The Organization for Economic Co-operation and Development (OECD) were compared. In order to determine the sustainability of the policy design option implemented by South Africa, the policy design option was compared to that implemented by other jurisdictions namely, the United States of America, Mexico and Denmark. The opponents of sugar tax challengedthe implementation of initiatives and utilization of income generated from sugar tax in South AfricaItem Compliance of medical practitioners with diabetic treatment guidelines at Dr Yusuf Dadoo Hospital, West Rand Health District Gauteng(2024) Ohanson, N.J.Background: Diabetes (DM) is a common chronic condition. The prevalence is increasing globally and has become a common health care problem associated with multiple complications. Guidelines have been formulated to standardise care among people living with DM, with aim of optimising patient care and thus minimising the complications. Aim: The aim of this study was to assess how well health care practitioners in Dr Yusuf Dadoo Hospital complied with the most recent diabetic treatment guideline, SEMDSA 2017. Setting: This study was conducted in the out-patient department of Dr Yusuf Dadoo hospital in the Westrand Health district of Gauteng. Methods: A retrospective cross-sectional review of patient record living with diabetes was done. Three hundred and twenty-three Record of patients seen from August 2019 to December 2019 were reviewed and some of the basic variables were assessed according to the most recent diabetic treatment guidelines SEMDSA 2017. Results: Files were audited in 4 main categories. Comorbidities, Examinations. Investigations, presence of complications. In terms of monitoring parameters, only 40(12.4%) had HbA1c assessed 6monthly, with annual creatinine assessed in 179(55.4%) and lipogram 154(47.7%) of patients. More than 70% of patients had uncontrolled glycaemia. More than 70% of patients had uncontrolled glycaemia. The most frequently documented target organ screening/examinations were foot related at 8.7% (28) and all of them had established complications. Only 2 people were screened for erectile dysfunction. Conclusion: Adherence to DM treatment guidelines was found to be poor. Monitoring and control parameters were infrequently done as per guideline recommendation. The resultant effect are poor glycaemic control and therefore numerous complications. The study site and thus the West rand needs targeted strategies to improve medical practitioner adherence to guidelines including adequate interpretation of results, timely intervention, when necessary, as a way to improve DM care and thus minimise the risk of complications amongst patients in the districtItem An audit of children with Type 1 diabetes mellitus presenting to a tertiary institution in Johannesburg, South Africa(2024) Gray, MeghannAt initial diagnosis, the rate of diabetes ketoacidosis (DKA) varies between countries (15- 67%) and may be associated with a lack of awareness of early signs and symptoms. Objectives: To describe the demographic, anthropometric, clinical and biochemical characteristics of children presenting with Type 1 diabetes mellitus (DM). Methods: A retrospective review of Type 1 DM children's medical records admitted to CHBAH from 01 January 2009 to 31 December 2018 was conducted. This ten-year period was further subdivided into two groups (Group 1: 2009-2013 (n = 75); Group 2: 2014-2018 (n=78)) to assess annual follow-up visit data in Group 1 for five years per patient and to compare data between the Group 1 and 2 time periods. Statistical differences between groups were analyzed by Mann-Whitney U test or Student t-tests, and for between the years of follow-up (Group 1), the paired student t-test was used. Results: The total number of newly diagnosed Type 1 DM children was 153. The median age at presentation was 10.5 years (IQR 7.4-12.3), 56% females and 88% black. The mean WAZ and HAZ were -0.8 (SD ± 1.5) and -0.4 (SD ± 1.6) respectively. Sixty-five percent (n = 100) presented in DKA, 56% of those being severe with a higher prevalence of DKA in group 2 compared to group 1 (72% vs 59%; p=0.08). At presentation, the median HbA1c was 12.5% (IQR 11.1-14.3) and C-peptide was 0.2ug/L (IQR 0.1-0.4) (normal range 1.1-1.4). Anti-GAD antibodies were positive in 82% (n=82/101) of the results available. In Group 1, HbA1c increased at year 3 follow up with advancing pubertal status. Despite changing to more intensive insulin therapy, mean HbA1c remained unchanged over the 5 years of follow-up. Conclusion: The majority of newly diagnosed children presented in severe DKA, similar to Red Cross War Memorial Children's Hospital (2005-2009), with an increasing prevalence over the ten vii years, which could be attributed to the lack of awareness of Type 1 DM in our population. An education campaign is needed to improve community knowledge about diabetes.Item Characterising skeletopathy in an animal model of Type 2 diabetes(2024) Dlamini, Gcwalisile FrancesType two diabetes (T2D) is a chronic, progressive heterogonous syndrome with a genetic and environmental origin. It is now recognized as an epidemic with a high morbidity and mortality rate. The endocrinology of type 2 diabetes (T2D) and its predisposing factors have been studied extensively, while diabetic skeletopathy has received negligible research. Previous studies report that fractures in T2D vary with specific sub regions in bones, therefore prompting our study to focus mainly on the femoral head and neck as well as the humerus head. Femoral neck fractures are the commonest, followed by the proximal femur, distal radius and proximal humerus. Susceptibility to fracture is a sequelae of poor bone remodeling. Poor bone remodeling is established at molecular and cellular levels. It depends on the activity of osteoblasts, osteocytes and osteoclasts, which are under the influence of TGF-β1, a pro-osteogenic cytokine, together with BMP3, an anti-osteogenic cytokine.T2D induced bone marrow adipocity and the accumulation of AGEs in cortical bone have also been implicated in increasing susceptibility to fracture. It is still unclear how T2D affects molecular and cellular elements that culminate in weaker bones observed in diabetic patients. In addition, it is debatable if T2D affects the skeleton at disease onset or later in the disease. Therefore, this study aimed to characterize T2D induced skeletopathy and related it to age, in the Zucker Diabetic Sprague Dawley (ZDSD) rat, using the femur and humerus. This study initially confirmed the diabetic state by monitoring animal weights, fasting blood glucose levels, and fasting oral glucose tolerance tests (OGTTs) every fortnight. Then triglyceride levels and quantified serum levels of osteoregulatory hormones such as insulin and osteocalcin were monitored. To assess oxidative stress, Malondialdehyde (MDA) serum levels were also determined by ELISA. Once diabetes was successfully induced, rats were grouped according to strain and age at termination. Termination age was at 20 weeks and 28 weeks . The Sprague Dawley (SD) rats were v the controls, while the Zucker Diabetic Sprague Dawley rats (ZDSD) were the experimental groups. These were designated as SD20WK (n=8) and ZDSD20WK (n=7) respectively. Another batch was designated as SD28WK (n=8), and ZDSD (n=15) that were terminated at 28 weeks of age. The latter were further divided into moderate diabetes (ZDSD28WK-MOD) (n=9) and severe diabetes (ZDSD28WK-SVD) groups (n=6). Bilateral humeri and femora were harvested then fixed in 10% buffered formalin. Right proximal femora and humeri were scanned using a 3D-μCT scanner (Nikon XTH 225L) to analyse trabecular morphometric parameters, cortical bone area and medullary canal area. Biomechanical strength was analyzed by three point bending tests using a universal tensile tester. Left proximal femora and humeri were processed for histology. Some sections were stained with Haematoxylin and Eosin (H&E) to assess normal histologic morphology and adipocyte quantification. Remnant sections were immunolabelled using the anti-TRAP and anti-ALP antibodies for osteocyte and osteoblast quantification respectively, to assess osteolysis and osteogenesis. Immunolocalization of AGEs, TGF-β1 and BMP3 was also conducted to investigate their role in diabetic skeletopathy. We found that diabetes affected osteoblastogenesis as measured by ALP positive cells and bone marrow adipocytes. TRAP positive osteocytes numbers were increased in the presence of T2D, suggesting an increased osteolysis. There was reduced TGFB1 expression with increased BMP3 expression. The number of AGEs immuno-positive cells as well as its extracellular expression was increased. Our finding suggest that osteoblast and osteocyte numbers are regulated by TGFβ1 and BMP3 in both bones, under the influence of AGEs. Our findings from osteometry, 3-point bending tests and Micro CT support that diabetes weakens bone. The diabetic effect results in lighter, shorter hollow bones that perform poorly under loading, as well as exhibit unfavourable trabeculae microarchitecture. Our findings confirm that T2D causes increased fragility in the proximal femur and humerus as well the mid-diaphysis. These perturbations occur early and late in the disease, and they are also exacerbated by the presence of hyperglycemia. vi We conclude that the ZDSD rat can be used as a translational model for diabetic skeletop