Type-2 diabetes is one of the most prevalent non-communicable diseases globally. The prevalence has increased rapidly in both developed and developing countries. Type-2 diabetes has become epidemic in China in the past three decades. With a relatively low obesity prevalence compared to western countries, such as the United States, the question has arisen as to why people in China are so susceptible to diabetes, but few studies have answered this question definitively. Asians have lower muscle mass than Caucasians which could be one possible explanation. This study aims to test the hypothesis that pubertal muscle mass acquisition, under the influence of testosterone, may be a risk factor for diabetes. This study recruited from the population-representative Chinese “Children of 1997” birth cohort with 8327 participants (88% of all infants born in April and May 1997) in Hong Kong. Participants were aged 15 years at the time of this study. The main objective was to examine the association of pubertal muscle mass with diabetes risk factors, and to examine determinants of pubertal muscle mass in this non-western setting. In June to August 2012, 502 participants from “Children of 1997” were recruited to complete a health assessment follow up at the Active Health Clinic in University of Hong Kong, including a questionnaire, blood tests and a physical examination. Multivariable linear regression was used to assess the associations of: (1) testosterone and pubertal muscle mass with diabetes risk factors, including fasting glucose, fasting insulin and homeostasis model assessment -insulin resistance (HOMA-IR), and any mediation of the association of testosterone with diabetes risk factors by pubertal muscle mass, and (2) environmental influences, including intergenerational influences, proxied by mother’s place of birth, and current life style influences (meat consumption and physical activity), with pubertal muscle mass. Higher pubertal testosterone was associated with lower fasting glucose (-0.008, 95% confidence interval (CI) -0.015 to -0.002), fasting insulin (-0.44, 95% CI -0.57 to -0.31) and HOMA-IR (-0.090, 95% CI -0.12 to -0.063) after adjusting for potential confounders, i.e, sex, birth weight, highest parental education, mother’s place of birth and physical activity. The association was partially mediated by skeletal muscle mass and body fat percentage. Skeletal muscle mass was negatively associated with fasting glucose (-0.017, 95% CI -0.025 to -0.009), insulin (-0.876, 95% CI -1.033 to -0.719), and HOMA-IR (-0.180, 95% CI -0.214 to -0.147) after adjusted for potential confounders. High meat consumption (0.176, 95% CI 0.000 to 0.351) and physical activity (0.157, 95% CI 0.059 to 0.254) were both associated with higher skeletal muscle mass in adolescents; however birth weight and mother’s place of birth had no influence on pubertal skeletal muscle composition. Higher pubertal muscle mass and testosterone are association with better glucose metabolism in adolescence. Food intake and physical activity may also influence the development of skeletal muscle, thus adolescence may be a sensitive period for the development of diabetes where interventions to increase muscle mass could have long-term protective effects. / published_or_final_version / Public Health / Master / Master of Philosophy

published_or_final_version / abstract / Medicine / Master / Doctor of Medicine

Pregestational and gestational diabetes (GDM) places the mother and her offspring at an increased risk for later development of insulin resistance and type 2 diabetes. Oxidative stress may mediate long-term disturbances in glucose homeostasis associated with type 2 diabetes and the metabolic syndrome. This thesis describes a cross-sectional study examining serum concentrations of free radical generated oxysterols as markers of oxidative stress in a cohort of teenage daughters from pregnancies with and without GDM. Daughters of GDM-pregnancies had a tendency of higher levels of serum oxysterols (7beta-hydroxycholesterol); however, this difference was not statistically significant after adjustment for total cholesterol. Serum oxysterols were significantly correlated with obesity measures such as waist circumference and BMI, which likely accounted for the tendency for higher measures of oxysterol concentrations in the GDM daughters. Oxysterols represent potentially important biomarkers for oxidative stress in adolescent girls as their levels track with the metabolic syndrome risk factors. / Le diabète pré-gestationnel et le diabète de gestation (DG) augmentent le risque dedéveloppement d'une future résistance à l'insuline et de diabète de type 2 autant pourla mère que pour l'enfant. Le stress oxydatif est un facteur potentiel impliqué dans ledéséquilibre du glucose sanguin associé au diabète de type 2 et au syndromemétabolique. La présente thèse est une étude sectionnelle croisée, ayant pour but demesurer des marqueurs du stress oxidatif, notamment la concentration des oxystérolsgénérés par les radicaux libres dans le sérum d'adolescentes, nées de mères ayantprésenté ou non un diabète de gestation. Nos résultats montrent des concentrationsd'oxystérols (7P-hydroxycholesterol) plus élevées dans le sérum de filles issues degestations diabétiques à comparer aux filles de mères n'ayant pas eu de DG.Cependant, la différence entre les deux groupes n'était pas statistiquementsignificative après un ajustement au cholestérol total. La concentration d'oxystérolsétait significativement corrélée aux marqueurs d'obésité, notamment la circonférencede la taille et l'index de masse corporelle, possiblement à l'origine de la tendance desoxystérols à être plus élevés dans le cas des adolescentes issues de gestationsdiabétiques.

Inflammation contributes to the etiology of type 2 diabetes (T2D) and cardiovascular disease (CVD). Therefore, it is of interest to investigate how diet relates to plasma inflammatory proteins, particularly whole grain and fibre intakes, as these factors have been associated with lower CVD and T2D risk. Only a limited number of observational studies have examined these relationships. The objective of this study was to investigate the cross-sectional relationships of whole and refined grain and dietary fibre intakes with plasma inflammatory proteins. There was a strong inverse relationship between whole grain intake and plasminogen activator inhibitor type 1 (PAI-1) (β =-0.102; SE=0.038; p=0.0077), and a positive relationship between refined grain intake and PAI-1 (β=0.076; SE=0.034; p=0.0251). Additionally, dietary fibre was related to lower concentrations of C-reactive protein (β=-0.034; SE=0.010; p=0.0008) and fibrinogen (β=-1.207; SE=0.505; p=0.0171). This research suggests that whole and refined grain and fibre intakes may influence inflammatory protein concentrations.

Inflammation contributes to the etiology of type 2 diabetes (T2D) and cardiovascular disease (CVD). Therefore, it is of interest to investigate how diet relates to plasma inflammatory proteins, particularly whole grain and fibre intakes, as these factors have been associated with lower CVD and T2D risk. Only a limited number of observational studies have examined these relationships. The objective of this study was to investigate the cross-sectional relationships of whole and refined grain and dietary fibre intakes with plasma inflammatory proteins. There was a strong inverse relationship between whole grain intake and plasminogen activator inhibitor type 1 (PAI-1) (β =-0.102; SE=0.038; p=0.0077), and a positive relationship between refined grain intake and PAI-1 (β=0.076; SE=0.034; p=0.0251). Additionally, dietary fibre was related to lower concentrations of C-reactive protein (β=-0.034; SE=0.010; p=0.0008) and fibrinogen (β=-1.207; SE=0.505; p=0.0171). This research suggests that whole and refined grain and fibre intakes may influence inflammatory protein concentrations.

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Master of Public Health / OBJECTIVES: In Australia, diabetes causes significant morbidity and mortality. Whilst the need to prevent diabetes and its complications has been widely recognised, the capacity of health care systems - which organise diabetes care - to facilitate prevention has not been fully established. METHODS: A series of seven population-based case-control studies were used to examine the effectiveness of the Australian health care system and its capacity to manage diabetes. Six of the studies compared the patterns of care of patients who had developed advanced diabetes complications in 2000 (cases), to similar patients who remained free of the condition (controls) across Australia and for various risk groups. A secondary study investigated the role of treating GPs in the development of the outcome. RESULTS: A strong relationship between the patterns of care and the development of advanced diabetes complications was found and is described in Chapter 4. In Chapter 5, this same relationship was investigated for each Australian state and territory, and similar findings were made. The study in Chapter 6 investigated whether late diagnosis or the patterns of care was the stronger risk factor for advanced diabetes complications, finding that the greatest risk was associated with the latter. In Chapter 7 the influence of medical care during the pre-diagnosis period was explored, and a strong relationship between care obtained in this period and the development of advanced complications was found. In Chapter 8, which investigated the role of socio-economic status in the development of advanced complications, found that the risk of advanced diabetes complications was higher in low socio-economic groups. Chapter 9 investigated geographic isolation and the development of advanced diabetes complications and found that the risk of advanced complications was higher in geographically isolated populations. Finally, Chapter 10, which utilised a provider database, found that some GP characteristics were associated with the development of advanced diabetes complications in patients. CONCLUSION: A number of major risk factors for the development of advanced complications in Australia was found. These related to poorer diabetes management, later diagnosis, low socioeconomic status and geographic isolation. Strategies must be devised to promote effective diabetes management and the early diagnosis of diabetes across the Australian population.

Daughters of gestational diabetes (GDM) affected pregnancies are at greater risk for the development of type 2 diabetes mellitus (DM) later in life. Adiponectin is an early marker of DM risk. Dietary fat quality has been proposed to be involved in the development of insulin resistance. Plasma fatty acids are a marker of recent dietary exposure. The objectives of this research were to determine whether differences in adiponectin exist in daughters of GDM pregnancies, and to describe how dietary fatty acids impact adiponectin concentrations. Fasting adiponectin and plasma fatty acids were examined for 180 adolescent daughters born to mothers with and without GDM. No differences were observed in adiponectin between study groups, however; a significant difference was detected upon comparison of daughters from mothers who were presently diabetic with those from healthy mothers. The association between fatty acids and adiponectin varied by visceral adiposity. Adiponectin was inversely associated with monounsaturated and omega-3 (n-3) fatty acids in the high waist group. Further knowledge on the interactions between fatty acids, desaturase activity and adiponectin would be helpful in planning early interventions for individuals at risk for diabetes.

Master of Public Health / OBJECTIVES: In Australia, diabetes causes significant morbidity and mortality. Whilst the need to prevent diabetes and its complications has been widely recognised, the capacity of health care systems - which organise diabetes care - to facilitate prevention has not been fully established. METHODS: A series of seven population-based case-control studies were used to examine the effectiveness of the Australian health care system and its capacity to manage diabetes. Six of the studies compared the patterns of care of patients who had developed advanced diabetes complications in 2000 (cases), to similar patients who remained free of the condition (controls) across Australia and for various risk groups. A secondary study investigated the role of treating GPs in the development of the outcome. RESULTS: A strong relationship between the patterns of care and the development of advanced diabetes complications was found and is described in Chapter 4. In Chapter 5, this same relationship was investigated for each Australian state and territory, and similar findings were made. The study in Chapter 6 investigated whether late diagnosis or the patterns of care was the stronger risk factor for advanced diabetes complications, finding that the greatest risk was associated with the latter. In Chapter 7 the influence of medical care during the pre-diagnosis period was explored, and a strong relationship between care obtained in this period and the development of advanced complications was found. In Chapter 8, which investigated the role of socio-economic status in the development of advanced complications, found that the risk of advanced diabetes complications was higher in low socio-economic groups. Chapter 9 investigated geographic isolation and the development of advanced diabetes complications and found that the risk of advanced complications was higher in geographically isolated populations. Finally, Chapter 10, which utilised a provider database, found that some GP characteristics were associated with the development of advanced diabetes complications in patients. CONCLUSION: A number of major risk factors for the development of advanced complications in Australia was found. These related to poorer diabetes management, later diagnosis, low socioeconomic status and geographic isolation. Strategies must be devised to promote effective diabetes management and the early diagnosis of diabetes across the Australian population.

An accumulating evidence-base indicates that internalizing mental health disorders in adulthood are causally associated with cardiovascular diseases (CVD) and type-2 diabetes (T2DM). It is plausible, however, that the relationship between mental and cardiometabolic ill-health becomes established long before adulthood, and that externalizing problems (the other central domain of common psychopathology) are also involved. These questions, as well as questions on the mechanisms that underlie the relationships, have been insufficiently investigated. The overarching goal of this dissertation was to expand current knowledge on how common mental health problems increase cardiometabolic risk over the life course. First, the prospective association between childhood internalizing (emotional problems) and externalizing problems (hyperactivity and conduct problems) with CVD and T2DM risk in adolescence was assessed in data from the Avon Longitudinal Study of Parents and Children (ALSPAC, N=7,730). Results showed that hyperactivity problems were associated with insulin resistance (high HOMA-IR); that hyperactivity and conduct problems were each associated with high triglyceride levels; and that emotional problems were inversely associated with high triglyceride levels. These results suggest that childhood externalizing problems are an early life risk factor for CVD and T2DM and that childhood internalizing problems are not a risk factor or, that risk in these children does not become apparent until after adolescence. Second, the mechanisms underlying the prospective association of childhood hyperactivity and conduct problems with high levels of triglycerides in adolescence were investigated using causal mediation methods. Results showed that despite being associated with hyperactivity and with conduct problems, body mass index and lifestyle health behaviors including sleep, diet, physical activity, alcohol, and smoking, together these variables, as measured, mediated only 19.6 % and 19.3% of the associations of hyperactivity and conduct problems with triglycerides, respectively. These results would suggest that mechanisms other than body adiposity and unhealthy behaviors are also involved and that those mechanisms have a larger role in mediating these relationships. Alternatively, It is possible that the observed small role of health behaviors is due to error in measurement and therefore improving measurements for health behaviors should be a central focus of future work. Third and last, a systematic review of the literature on the relationship between childhood externalizing problems with CVD and T2DM risk was conducted. Studies were graded for propensity to bias. Evidence was summarized and assessed for consistency. Results strongly supported positive associations of externalizing problems with insulin resistance, T2DM, and with increased blood lipids among children and adolescents. Evidence suggested that associations are at least partly independent of body adiposity. Evidence provided mix support for the associations with T2DM and blood lipids in adults and with other outcomes in children or adults. Studies in children tended to be cross-sectional and to use valid and reliable assessment methods, whereas studies of adults tended to be prospective and to rely on less-valid, less reliable assessment methods. These results warrant more research, specifically prospective studies that track children into young adulthood, that employ well-validated measures of externalizing behaviors, that rely on repeated assessments of T2DM and CVD risk throughout follow-up, and that investigate mechanisms other than body adiposity and health behaviors. Overall, this dissertation has found that childhood externalizing problems are prospectively associated with elevated CVD and T2DM risk, specifically with elevated risk of increased levels of blood lipids and insulin resistance. Unlike studies in adults, this dissertation does not support a role of internalizing problems as risk factors. Among children with externalizing problems, risk becomes evident before adolescence and appears to be largely driven by pathways independent of unhealthy behaviors and body adiposity. Implications of this research’s findings for health practice were proposed. This dissertation identified several gaps and methodological shortcoming in the extant literature. Recommendations were made for future research, including fundamental next questions to investigate, and study designs and methodologies that are best suited to tackle those questions.