Search

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.

Cardiovascular diseases and type 2 diabetes mellitus are highly prevalent chronic diseases. They have similar risk factors and are preventable with lifestyle changes. Mobile applications (apps) can provide behaviour change interventions widely at a relatively low cost. This thesis aimed to identify risk assessment tools suitable for laypeople to determine their cardiovascular and diabetes risk, develop an app for risk awareness and prevention of the two diseases, and test the feasibility of the mobile health intervention. Chapter 2 contains a rapid review of cardiovascular and diabetes risk models. In Chapters 3 and 4, two models based on lifestyle-related risk factors were externally validated in a large Australian cohort. In Chapter 5, the literature was systematically reviewed to evaluate the effectiveness of preventive mobile interventions for the two diseases. Chapter 6 comprises a cross-sectional analysis of mobile health use in older Australians. Chapter 7 describes the development process of a smartphone app according to a framework and iterative testing of the app's usability in a small sample. In Chapter 8, the feasibility of the intervention was assessed over three months with app data and a survey. The rapid review in Chapter 2 included the risk models routinely used in Australian clinical practice and two lifestyle-based risk models without Australian validation. In Chapters 3 and 4, the lifestyle-based diabetes risk model performed satisfactorily, but the cardiovascular model predicted a 5-year risk poorly. The systematic review in Chapter 5 found some indications for the effectiveness of mobile interventions in preventing cardiovascular disease and diabetes. The cross-sectional analysis in Chapter 6 showed low mobile health use in older Australians. The app developed in Chapter 7 encompassed four modules: risk assessment, goal setting, self-monitoring, and health information. Usability testing participants found the app easy to use. In the feasibility study in Chapter 8, 20 out of 46 participants never used the app, 15 dropped out, and 8 used the app weekly. The overall app quality rating was satisfactory. Although the intervention was easy to use, the levels of adoption and sustained use were low. Further research is needed to adapt the app to make it more appealing and provide greater benefits. The potential utility of digital health interventions is vast, but they still need to live up to their expectations.

Background: Obesity is the most relevant overnutrition disease worldwide and is associated to different metabolic disorders such as insulin resistance and type-2 diabetes. Low glycemic load foods and diets and moderately high protein intake have been shown to reduce body weight and fat mass, exerting also beneficial effects on LDL-cholesterol, triglyceride concentrations, postprandial glucose curve and HDL-cholesterol levels. The present study aimed at studying the potential functionality of a series of low glycemic index products with moderately high protein content, as possible coadjuvants in the control of type-2 diabetes and weight management following a chronologically planned snacking offer (morning and afternoon). Methods: The current trial followed a single group, sequential, longitudinal design, with two consecutive periods of 4 weeks each. A total of 17 volunteers participated in the study. The first period was a free living period, with volunteers' habitual ad libitum dietary pattern, while the second period was a free-living period with structured meal replacements at breakfast, morning snack and afternoon snack, which were exchanged by specific products with moderately high protein content and controlled low glycemic index, following a scheduled temporal consumption. Blood extractions were performed at the beginning and at the end of each period (free-living and intervention). Parameters analysed were: fasting glucose, insulin, glycosylated hemoglobin, total-, HDL- and LDL-cholesterol, triglyceride, C - reactive protein and Homocysteine concentrations. Postprandial glucose and insulin were also measured. Anthropometrical parameters were monitored each 2 weeks during the whole study. Results: A modest but significant (p = 0.002) reduction on body weight (1 kg) was observed during the intervention period, mainly due to the fat mass loss (0.8 kg, p = 0.02). This weight reduction was observed without apparently associated changes in total energy intake. None of the biochemical biomarkers measured was altered throughout the whole study. Conclusions: Small changes in the habitual dietary recommendations in type-2 diabetes patients by the inclusion of specific low-glycemic, moderately high-protein products in breakfast, morning and afternoon snacks may promote body weight and fat-mass loss, without apparently altering biochemical parameters and cardiovascular risk-related factors.