Proefschrift Universiteit van Amsterdam. / Met lit. opg. - Met samenvatting in het Nederlands.

Thesis (Ph. D.)--University of Washington, 1987. / Vita. Bibliography: leaves [116]-129.

Proefschrift Universiteit Maastricht. / Met bibliogr., lit. opg. - Met samenvatting in het Nederlands.

Proefschrift Universiteit Maastricht. / Teksten in het Engels en Nederlands. - Auteursnaam op omslag: Henk van Dam. Met bibliogr., lit. opg. - Met samenvatting in het Engels.

Proefschrift Universiteit Maastricht. / Auteursnaam op omslag: Lars Borghouts. Met bibliogr., lit. opg. - Met samenvatting in het Nederlands.

Background: The epidemic of type 2 diabetes poses an enormous and growing burden on health care globally. While the prevalence of diabetes is increasing worldwide, the developing countries will bear the greatest burden of this disease. Diabetes is one of the most common causes of kidney failure and nephropathy is a strong predictor of cardiovascular complications and death in these patients. Microalbuminuria represents a latent and early pre-symptomatic phase of nephropathy which can be stopped from progressing to an advanced stage if detected and treated early. The cost effectiveness of this screening and intervention has been researched and proven in the developed world, however similar studies in developing countries are non-existent. Microalbuminuria is not currently tested for in the public primary care sector. Aim and objectives: The aim was to assess the feasibility of introducing a screening test for microalbuminuria and the associated costs and consequences at Elsies River Community Health Centre (CHC) in the Metropolitan District of Cape Town. The objectives of the study are to assess the feasibility of implementing the test in our context, to assess any additional cost to the health services, to assess any measurable benefits in the quality of care for the patients, to extrapolate the likely long term consequences in terms of health outcomes, use of resources and costs and to make a policy recommendation to the Department of Health. Method: A cost and consequence study that describes the introduction of microalbuminuria testing in a cohort of type 2 diabetic patients at Elsies River Community Health Centre, Metro District Health Services, Cape Town, South Africa. Point of care status analyser microalbuminuria screening was introduced to the CHC after training of the chronic care team, and their fidelity to the protocol measured. All patients who met the inclusion criteria were screened. Patients whose first results were abnormal had a repeat test after 3-6 months, if both results were abnormal patient was diagnosed microalbuminuria positive, however a patient with a second normal result required a third test. Interventions included addition of an Angiotesin Converting Enzyme inhibitor to their treatment, more intensive glycaemic, blood pressure or lipid control via medication or lifestyle changes and treatment adherence health education. Field notes were taken by the researcher during visits and a recorded focus group interview conducted with the health workers to explore their views on the feasibility of the screening and intervention. Cost was assessed by the estimation of the additional resources required and the likely long term health outcomes extrapolated from available data and literature. Results: 15.2% of the sample population was noted to be microalbuminuria positive and they all received interventions. Additional cost required to screen a cohort of 100 patients was R1,109.40 per annum, out of which 15 patients at risk of developing nephropathy were identified and the cost of treating these patients was R1,393.20 for the first year. Qualitative data revealed that the test and interventions are feasible with an additional cost of staff time, medication and other materials which have been included in the cost above. Conclusion: This study represents the first attempt to successfully introduce screening for microalbuminuria in our public primary health care context. The chronic care team showed reasonable fidelity to the protocol and demonstrated the feasibility of screening and treating patients. The balance of costs and long term benefits suggests that this represents excellent value for money in a South African primary care setting.

Interest in the ketogenic diet and its potential to treat obesity and type 2 diabetes has been steadily growing in recent years. With a very limited amount of calories coming from carbohydrates (typically < 50 gm/day), and the majority of calories coming from fat, this diet leads to a states of physiological ketosis, in which ketone bodies replace glucose as the primary source of energy. Early clinical trials found this to lead to a spontaneous reduction in calories consumed, and it has been suggested that a state of ketosis has appetite suppressing properties. There are a few studies evaluating self-reported decrease in hunger while consuming a ketogenic diet, as well as the changes in hormone levels associated with appetite, but this evidence is limited. The primary determinant of weight change is the difference between calories consumed and calories burned, however there is some suggestion that the macronutrient composition of the ketogenic diet may have a specific metabolic advantage for weight loss separate from the total number of calories in deficit. Multiple diet comparison studies have found the ketogenic diet to be effective for weight loss in the short term, particularly when compared to low fat diets. It is questionable whether the ketogenic diet is sustainable in the long term, particularly without frequent nutritional counseling and monitoring. Still, there is preliminary evidence that the ketogenic diet can lead not only to a large amount of weight loss, but may also be effective in treating and reversing type 2 diabetes. Clinical trials have shown decreases in HbA1c, fasting glucose, and reduction of antiglycemic medication requirements, though it is unclear if these effects are primarily due to weight loss itself, or the specific composition of the ketogenic diet. These benefits need to be weighed against the risks, and a common criticism is its high fat content which can adversely affect serum lipid levels and thus risk of cardiovascular disease. Consuming a ketogenic diet with a high intake of saturated fat has been found to increase LDL cholesterol, however this effect can be mitigated by favoring polyunsaturated or monounsaturated fats instead. While the above findings provide a preliminary understanding of the effects of the ketogenic diet, more research is needed to further elucidate the effectiveness and safety of the diet for treating obesity and type 2 diabetes.

The prevalence of overweight and obesity in adolescents has increased dramatically over the past few decades. This increase is associated with a higher risk of developing Type 2 Diabetes Mellitus (T2DM). The "R.U.A. Healthy Kid?" program was created to target modifiable risk factors related to development of T2DM. This study specifically focuses on the influence of snacking habits. Researchers have documented an increase in snacking occasions and preference for low-nutrient snacks among adolescents. Many adolescent diabetes prevention programs target dietary behaviors, but none have used the Stages of Change as a theoretical framework to promote behavior change. The purpose of this study was to determine the impact of a three month community-based intervention on snack consumption and snacking habits of adolescents with risk factors for T2DM. Additionally, it explored the use of the Stages of Change model to understand how the intervention impacted adolescents' movement through the stages, and if reported stage was related to reported snack consumption and snacking habits. At completion of the study, the majority of participants reported forward progress in stages of change, indicating they were actively making changes in regards to high-nutrient (healthy) snacking. There was also a decrease in low-nutrient (unhealthy) snack consumption, and a significant improvement in overall snacking score. Participants reported several factors influenced their snack choice including hunger, taste, and availability. These findings are important to the development of appropriate programs to encourage healthy dietary behaviors at a young age.

Aims: This PhD project was designed under two studies, the genetic association study to investigate a genetic component or a genetic pathway that might be associated with both schizophrenia and type-2 diabetes (T2D). The gene functional study to explore whether clozapine could affect expression of the genes associated with obesity and T2D. Methods: In genetic association study, a total of 17 single nucleotide polymorphisms (SNPs) were genotyped in the PPARG, PLA2G4A, PTGS2 and AKT1 genes in 221 British nuclear families. In the gene functional study, U937 cells were treated with clozapine (1g/ml and 2g/ml) for 48 hours and 96 hours. Quantitative real-time PCR analysis was used to measure the mRNA expression levels of the genes of interest in clozapine-treated and untreated cells. Results: Eight SNPs tested across the PPARG gene did not show allelic association with schizophrenia. An association was detected at rs2745557 in the PTGS2 locus (2=4.19, p= 0.041) and rs10798059 in the PLA2G4A locus (2=4.28, p=0.039), but these associations did not survive after 10,000 permutations (global p=0.246). Allelic association for the AKT1 gene was detected at rs1130214 (2=6.28, p=0.012) and at rs11847866 (2=4.64, p=0.031) only although the global p-value of overall associations for the AKT1 was 0.059 after 10,000 permutations. Haplotype analysis showed a disease association for the rs1130214-rs2494746-rs11847866 haplotypes (2= 10.18, df= 4, p=0.037), of which the T-G-A haplotype was excessively transmitted (2=6.93, p=0.008) and this haplotypic association survived the Bonferroni correction (p=0.04). The expression of the MTCH2 gene showed a significant decrease in mRNA expression (combined p=0.001) and that of the PPARG gene showed a significant increase (combined p=0.005) in the cells treated with 1g/ml clozapine for 96 hours. Conclusions: The present results support the AKT1 gene association with schizophrenia as reported in previous studies; both the MTCH2 and PPARG genes may be involved in the development of clozapine-induced obesity and in an increased risk of T2D.

In the past 30 years the prevalence of obesity has almost trebled resulting in an increased incidence of type 2 diabetes mellitus (T2DM) and other co-morbidities. Visceral adipose tissue is believed to play a vital role in these conditions, but underlying mechanisms remain unclear. A close association exists between obesity, diabetes and oxidative stress, resulting in increased reactive oxygen species formation. The experiments in this thesis address this by searching for possible biochemical changes which may be specific for the onset of obesity related T2DM, as well as looking for genetic alterations at molecular and gene expression levels. This thesis also explored various techniques such as polymerase chain reaction (PCR), colorimetric assays and real-time RT-PCR. The aim was to investigate the role of adipose tissue in obesity and T2DM, focusing on markers of oxidative stress and gene expression in human visceral adipose tissue from subjects categorised as lean, obese and obese with T2DM. This cross-sectional study measured two markers of oxidative stress, two markers of DNA damage, gene expression analysis and identification of genes associated with T2DM and obesity. Specific gene sequencing was carried out on the glutathione reductase gene to determine possible gene variants. Results showed a paradoxical decrease in adipose markers of oxidative stress in subjects with obesity and T2DM. There appeared to be a protective mechanism in these subjects, displaying reduced levels of oxidative stress compared to other groups. This could be due to a significant proportion of these subjects being on ACE inhibitor and statin therapy, which may be confounding results and minimising the effects of the oxidative burden. Additionally, the same subjects showed an increased expression of the glutathione reductase gene. It is difficult to conclude if the decreased levels of oxidative stress in these subjects were a result of the increased glutathione reductase expression in the visceral adipose tissue or if there remains an unseen factor influencing the dramatic expression change seen in this group of subjects. No glutathione reductase gene variants were identified in these samples. This analysis highlighted that within this sample set, the impact of oxidative stress is in fact reversible as the antioxidant capacity in these subjects is evident, and in combination with correct drug therapy it may be possible to combat oxidative burden and reduce the subsequent damage inflicted upon the cells.