Thesis (MTech (Biomedical Technology))--Cape Peninsula University of Technology, 2016. / The early detection of individuals who are at risk of developing type 2 diabetes mellitus (T2DM) would decrease the morbidity and mortality associated with this disease. DNA methylation, the most widely studied epigenetic mechanism, offers unique opportunities in this regard. Aberrant DNA methylation is associated with disease pathogenesis and is observed during the asymptomatic stage of disease. DNA methylation has therefore attracted increasing attention as a potential biomarker for identifying individuals who have an increased risk of developing T2DM. The identification of high risk biomarkers for T2DM could facilitate risk stratification and lifestyle interventions, which could ultimately lead to better ways to prevent, manage and control the T2DM epidemic that is rampant worldwide. The aim of the study was to investigate global DNA methylation as a potential risk factor for T2DM by studying the association between the global DNA methylation levels and hyperglycaemic states. A cross-sectional, quantitative study design, involving 564 individuals of mixed ancestry descent, residing in Bellville South, South Africa was used. Participants were classified as normal, pre-diabetic (impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT)) or diabetic (screen detected diabetic and known diabetics) according to WHO criteria of 1998. DNA was extracted from whole blood using the salt extraction method. The percentage global DNA methylation was measured by an enzyme-linked immunosorbent assay (ELISA). The association between global DNA methylation and hyperglycaemia, as well as other biochemical markers of T2DM was tested in a robust linear regression analysis adjusted for age, gender and smoking.

Obesity and type-2 diabetes are major global health crises. The synthetic retinoid compound 4-hydroxy(phenyl)retinamide (Fenretinide, FEN), has been shown to inhibit adiposity and reverse insulin resistance in pre-clinical studies. Fenretinide acts via several different mechanisms, including induction of retinoid signalling and increased hepatic lipid oxidation to exert its metabolic effects. However, the signalling mechanisms behind these effects have yet to be fully elucidated. A number of approaches were taken in this thesis to investigate the signalling mechanisms of Fenretinide. To characterise the relationship between Fenretinide and leptin signalling, Fenretinide treatment was administered in two different leptin-deficient mouse models. Fenretinide effects on hepatic signalling mechanisms were further characterised by performing global transcriptomics analysis in liver from mice receiving HFD ± Fenretinide. In this analysis, the important metabolic hormone fibroblast growth factor (FGF) 21 was identified as a novel retinoid-dependent target of Fenretinide signalling, which was further characterised in multiple mouse models. Retinoic-acid receptor-specific ChIP-sequencing was performed in order to identify other liver genes that are regulated by Fenretinide via retinoid-dependent signalling mechanisms. This work has shown that the beneficial effects of Fenretinide on adiposity occur via a mechanism independent of that through which Fenretinide mediates effects on glucose homeostasis. Fenretinide effects on insulin sensitivity and glucose homeostasis are most likely mediated via the inhibition of ceramide synthesis in the liver and other metabolically active tissues. This work also shows that Fenretinide can normalise the effects of chronic HFD-feeding by targeting the expression of a set of PPARα-target genes in the liver via a retinoid-dependent signalling mechanism. Overall, the work described in this thesis both uncovers more detail about the signalling mechanisms of Fenretinide and identifies novel target genes that may be exploited for the development of new therapeutics to treat obesity and type 2 diabetes.

Type II diabetes is fast becoming a growing problem in developed countries worldwide. Traditionally the median age for diagnosis was around sixty, but recent surveys have shown that the entire age distribution curve has shifted to the left. Western countries boast the worst statistics in which type II diabetes is being reported in children under the age of ten. At such a young age the disease often goes undiagnosed for long periods of time allowing considerable damage to occur. The incidence of type II diabetes is thought to be parallel with the growing rate of obesity associated with a characteristically unhealthy western diet. Type II diabetes is an extremely expensive disease to manage, and with the rapid growth of this pandemic our country will soon feel the economic burden of this disease. It is for this reason that cheaper medication needs to be investigated in the form of traditional plants, such as Sutherlandia frutescens. Prescription medication, such as tricyclic antidepressants, may also increase body weight or appetite thereby playing a role in obesity. The cause of weight gain in such cases may go unrecognized or lead to cessation of the medication with or without the practitioner’s knowledge or approval. It is therefore necessary to investigate the causative agents responsible for the excessive weight gain. Drinking water containing extracts of the S. frutescens, metformin (a well known type II diabetes medication) and amitriptyline (a common tricyclic antidepressant) was administered to three groups of ten male Wistar rats. The control group received water without any medication. The rat’s weight and food consumption was monitored throughout the trial and their oxygen consumption was also determined. Rats were sacrificed after four months of medicinal compliance and glucose uptake, in the presence and absence of insulin, was tested in epididymal fat, liver and muscle. Fasting plasma glucose levels, lipoprotein, cholesterol and triglyceride concentrations were also determined.

Abstract The markers of microvascular complications of type 1 diabetes were evaluated in adolescents in a cross sectional survey of 100 out of 138 eligible patients aged 9-19 years with a duration of diabetes over two years who visited the Paediatric Outpatient Clinic at Oulu University Hospital in 1997-1999, and one hundred healthy controls. Two patients in early or mid-puberty had non-proliferative diabetic retinopathy, but no other signs of microvascular complications. The five patients with persistent microalbuminuria were all girls; one prepubertal, one late pubertal and three postpubertal. Their mean glycated haemoglobin A1c (HbA1c) was higher, but they had a similar duration of diabetes and age distribution to those without microalbuminuria. The adolescent patients were predisposed to higher fasting serum total and low-density lipoprotein cholesterol and triglyceride levels and higher diastolic blood pressure than the control subjects. The proportional total body fat was highest in the girls with diabetes by the end of puberty, while serum leptin levels did not differ between the patients and healthy controls. The patients had low fasting serum insulin levels and high insulin-like growth factor-binding protein 1 levels, related to hypoinsulinaemia. Distal motor nerve function in the lower extremities were already affected before puberty, and distal and proximal nerve function deteriorated as puberty advanced. Ten patients had neurophysiologically confirmed distal diabetic polyneuropathy, and they were older and they had longer duration of diabetes and higher HbA1c than patients without polyneuropathy. Although cardiovascular function was in the main well preserved in the adolescents with type 1 diabetes, the power spectrum analysis of heart rate variability showed attenuated autonomic nervous system reactivity. Taken together these data show that a relatively small proportion of adolescents with type 1 diabetes have signs of microvascular complications. The prevalences of diabetic retinopathy, persistent microalbuminuria and distal diabetic polyneuropathy were 2%, 6% and 10%, respectively. Pubertal maturation seems to promote the progression of early signs of microvascular complications in patients affected by type 1 diabetes.

Type 2 Diabetes Mellitus (Type 2 DM) is present in the populations of almost all the countries in the world and is a significant disease burden in most developed countries. Evidence suggests that populations in Africa develop Type 2 DM at an increasing rate as they reject their traditional lifestyles. Furthermore, newly released figures by the Medical Research Council of South Africa indicate that diabetes is the 10th most common cause for total life years lost in females in South Africa. Exercise is a low cost, non-pharmacological intervention that has been shown to be effective in metabolic control. Exercise is still vastly under-utilised in the management of Type 2 DM, especially in urban black females with Type 2 DM. This study was designed to determine the effectiveness of an exercise intervention to decrease haemoglobin A1c (HbA1c) over period of 12 weeks in Type 2 DM black female subjects, aged 40to 65 years. This study consisted of three phases. Data captured in the first two phases were utilised to plan the exercise intervention. Questionnaires and focus groups were used in the first two phases of the stud. The final phase of the study consisted of a randomized controlled trial. For this phase 157 female subjects who were recruited at the Mamelodi hospital diabetes outpatient clinic, were randomized to either an experimental or a control group. It was found that the subjects had little knowledge about their disease and that they lead a sedentary lifestyle. Subjects felt that Type 2 DM had a negative impact on their lives. Their attitudes bout Type 2 DM showed a dependence on health professionals and they disagreed with the attitude that they should be involved in decision-making about their health care. The results of the focus groups indicated that patients viewed walking and household chores as suitable exercise for them. Personal barriers to exercise were lack of knowledge, tiredness and health-related stress. Subjects expected that exercise would increase the functional capabilities, increase their knowledge and improve their well being. These findings were used to plan the exercise intervention, which consisted of a home-based exercise programme and fortnightly exercise sessions at the Mamelodi hospital. Subjects also had to complete a diary of their physical activities at home. An analysis of co-variance (ANCOVA) was used to compare the experimental and control groups with respect to change in HbA1c and the secondary outcomes such as walking distance and quality of life outcomes. It was found that the exercise intervention was no more efficacious (p=0.05) than a supervised self-relaxation training intervention to decrease HbA1c, over a period of 12 weeks. The exercise group was however able to walk a significantly further distance (p<0.01) than the control group after the 12-week intervention. While not significantly different between groups (p=0.80), the positive well-being improved significantly within both groups (p<0.01). It is possible to improve blood glucose control by means other than medication in urban black female patients with Type 2 DM. The patients are willing to change their sedentary lifestyle to a more active one, but several environmental and personal barriers impact negatively o their attempts to do so. The role of the health care worker is to identify these barriers and to accompany the patient on the road to a healthier lifestyle. However, this population of women may need more assistance and support initially to take self-responsibility for their diabetes self-management eventually. / Thesis (PhD)--University of Pretoria, 2006. / Physiotherapy / unrestricted

Diabetes is a serious condition that affects all the body’s systems including kidneys, heart, eyes and limbs. This alone makes type II diabetes a life threatening disease; an expensive disease and economic burden that many individuals struggle to cope with.The rapid growth type II diabetes in South Africa is associated with the change of life style, and environmental factors brought by westernized way of life living in rural areas. Despite the technical advances in diagnosis and therapy of diabetes many people still use alternative forms of therapy due to the cost, traditional reasons and religion. Some of the people use the conventional medication together with the alternative therapy without informing their doctor and knowing the pathological changes. The aim of the study was to investigate pathological changes in male Wistar rats after co-treatment of type II diabetes with metformin and Sutherlandia frutescens and the possible synergistic and antagonistic effects. The thirty five rats were divided into five groups, seven in each group. There were two control groups and three test groups. Only the first control group was on a low fat diet (normal rat pellets) and second control group and test groups were on a high fat diet which induces obesity, insulin resistance and leads a typical prediabetic state for 12 weeks (Buettner et al., 2006). After 11.5 weeks medication was administered by oral gavaging to the test groups for 4 weeks and control groups received water. Blood was collected for determination of glucose, insulin, lipid profile and the concentrations of the liver enzymes. Pancreas, liver and kidney tissue were removed and used for histology. Urine was collected from the bladder for creatinine analyses. The plant + metformin group co-treatment was better in managing hyperglycemia, liver damages were minimal and also weight control was better when compared to metformin alone.

In Sub-Saharan Africa, the rapid increase in the prevalence of diabetes has resulted in significant public health and socioeconomic liability in the face of scarce resources. Faced with a growing pandemic of non-communicable diseases, developing countries need to be proactive in investigating alternative cost-effective interventions, with the primary aim being to minimize illness and maximize health benefits relative to the limited available resources. The aim of this research study was to quantify the economic impact of an exercise intervention as a preventative strategy for type 2 diabetes in a developing country. The research also sought to investigate if there was an economic case for physical activity as a primary and secondary preventative measure in the management of non-communicable diseases. The study was quantitative in nature and used both primary and secondary data to conduct the cost analysis. A questionnaire was administered to 40 patients at a diabetic clinic in a peri-urban community health care centre. Secondary data, consisting of clinic records and an extensive literature review, was used to source the remaining inputs needed for the cost analysis. Results revealed that the implementation costs of a physical activity intervention exceeded the costs of a pharmaceutical programme. Physical activity resulted in decreased productivity loss, with significant economic implications at a household level. Evidence reviewed in the literature suggested that physical activity could be used in primary prevention as a viable substitute to pharmaceutical therapy. For secondary disease prevention, however, physical activity was complementary in the production of health benefits, limiting disease progression and morbidity caused by illness. / Dissertation (MBA)--University of Pretoria, 2014. / lmgibs2015 / Gordon Institute of Business Science (GIBS) / Unrestricted

The worldwide prevalence of obesity and obesity-associated liver diseases have attracted great attention in the past decades. Obesity is an increasing health problem, which can induce a series of metabolic syndrome associated diseases, such as fatty liver disease, type 2 diabetes. The conventional causes for obesity, such as over-eating, sedentary life-style, and genetic factors, cannot fully explain the global rapid increase of obese population in the last few decades. It was found that the production of persistent organic pollutants (POPs) in the industry was closely correlated with the prevalence of obesity. POPs are organic chemicals that are resisted to degrade by various processes and widely applied in daily products to improve the quality of our life. 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) is the most abundant and toxic congener in the family of polybrominated diphenyl ethers (PBDEs), which are the commonly used flame retardants and listed as POPs in 2009. High concentration of BDE-47 has been found in indoor dust and marine fish in Hong Kong. Owing to their high lipophilic and persistent characters, BDE-47 is mainly accumulated in adipose tissue. Epidemiological data indicates that exposure to BDE-47 is associated with obesity and obesity-associated liver diseases. Therefore, based on published research, we hypothesize that BDE-47 exposure may increase the occurrence of obesity and aggravate the progression of obesity-associated fatty liver disease through promoting adipocyte differentiation and impairing lipid metabolism. To verify this hypothesis, mouse preadipocytes (3T3-L1 cells) were exposed to BDE-47 and differentiated into adipocytes. Excitedly, with BDE-47 exposure, more lipid droplets were formed and accumulated in the treated cells than that in untreated adipocytes (without BDE-47 exposure). Along with the increased content of triglyceride accumulation, augmented gene and protein levels of transcription factors (PPARγ and PGC-1α), and related genes (FABP4 and C/EBPα) were also detected in BDE-47 treated cells. In addition, the total production of reactive oxygen species (ROS), contents of lipid peroxidation and DNA oxidation were obviously increased in adipocytes treated with BDE-47 (10 μM). To explore how BDE-47 regulated the oxidative stress signal pathways, antioxidants of ROS sources were employed with BDE-47 exposure during adipocyte differentiation. Notably, mitochondrial respiration, xanthine oxidase and NADPH pathway were significantly influenced by BDE-47 exposure to generate ROS in the treated adipocytes. The effects of BDE-47 on mitochondrial respiration were also determined for further exploring the relationship between mitochondrial ROS and adipocyte differentiation. Significant elevation of mitochondrial ROS was detected in adipocytes exposed with BDE-47 (10 μM). Furthermore, to support the energy requirements for the growth of adipocytes during differentiation process, BDE-47 improved the mitochondrial metabolism for ATP production via increasing the spare mitochondrial respiration capacity. Inhibiting the mitochondrial ROS generation in BDE-47-treated adipocytes with antioxidant attenuated the generation of ROS and reduced the accumulation of lipid droplets as well. This phenomenon indicated that the ROS-induced by BDE-47 through mitochondrial chain was critical for adipocyte differentiation. Global metabolomic profiling based on high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) was performed on differentiated 3T3-L1 cells to reveal the metabolic changes induced by BDE-47. Twenty three significantly changed metabolites were identified in the adipocytes after BDE-47 exposure. The results of pathway analysis showed that purine and glutathione metabolism were the main impacted pathways and upregulated by BDE-47 treatment. In purine metabolism, increasing levels of adenosine monophosphate (AMP) and guanosine monophosphate (GMP) induced by BDE-47 led to the increment of inosine 5'-monophosphate (IMP) in adipocytes. These increases forwarded the pathway and caused high production of uric acid along with hydrogen peroxide, which contributed to the elevation of ROS after exposure to BDE-47. Inhibiting the synthesis of uric acid with antioxidant could significantly decrease the production of ROS, the levels of adipogenesis-related genes, and the accumulation of lipid droplets in BDE-47 exposed adipocytes. These results further demonstrated that exposure to BDE-47 promoted adipocyte differentiation via causing oxidative stress, upregulating purine metabolism, and increasing production of uric acid. Subsequently, C57BL/6J mouse model with diet interaction was employed to explore the obesogenic effects of BDE-47. Male C57BL/6J mice were fed with either a low-fat diet (LFD, 10% fat) or high-fat diet (HFD, 60% fat) for 15 weeks and subcutaneously injected with BDE-47 (7mg/kg [Low dose, L] or 70mg/kg [High dose, H]) or the vehicle weekly. It was found that exposure to BDE-47 (H) significantly led to the elevation of body weight and serum triglyceride content in HFD fed mice. Besides, the combination of BDE-47 and HFD also significantly increased the weight of white adipose tissue (WAT) and augmented the size of adipocytes in WAT. These have confirmed the obesogenic effects of BDE-47 in vivo. Additionally, BDE-47 (H) exposure significantly increased the accumulation of hepatic triglyceride content and lipid droplets accompanying with elevated inflammation in HFD fed mice, indicating the deterioration of hepatic steatosis in BDE-47 treated mice. Moreover, the integration analysis of lipidomic and gene expression revealed that BDE-47 up-regulated triglyceride synthesis but suppressed lipid exportation and β oxidation to impair the lipid metabolism and worsen the accumulation of hepatic lipid in HFD fed mice. In addition, the increase of liver fibrosis scars (the protein level of αSMA and collagens), serum transaminase levels, as well as lipid peroxidation have been detected in the mice with co-treatment of BDE-47 and HFD. BDE-47 exposure also increased the production of ROS and the levels of fibrotic genes in hepatocytes. However, in LFD with BDE-47 exposed mouse liver, we cannot observe such changes compared with the control (LFD-DMSO). Interestingly, the application of antioxidants reversed the BDE-47-induced fibrotic responses (the expression of αSMA and col3) in hepatocytes, which indicated that the increase of liver fibrosis scars was tightly associated with the level of oxidative stress. In conclusion, these results offered a new insight of lipid toxicities and underlying mechanism of BDE-47 induced obesity-related liver fibrosis. As far as we know, this is the first systematic study of the obesogenic effects and underlying mechanisms of BDE-47 in diet-induced mouse model. These results have showed the pathological roles of BDE-47 in the development of obesity and related liver diseases by an integration analysis of omics study and biological analysis in vivo and in vitro. Meanwhile, inhibitors were applied to investigate the mechanism of BDE-47-induced toxicity. Taken together, our results indicated that BDE-47 exposure could accelerate the development of obesity and aggravate the progression of fatty liver in obese mice via causing oxidative stress. This study may shed a light for an explanation for the worldwide prevalence of obesity and related liver diseases. Furthermore, this work reflects the potential of omics study and biological methods for toxicity assessment of environmental pollutants on human health. It would be helpful for the clinical diagnose and treatment.

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