Type 2 diabetes (T2D) is characterized by impaired beta cell function. The generation of various types of cellular stresses, including oxidative stress and ER stress, and the induction of cellular senescence can contribute to beta cell dysfunction. Recent studies have demonstrated associations between petrochemical exposure and beta cell dysfunction, particularly through induction of cellular stress. One class of compounds, commonly found in crude oil, are sulphur-containing heterocyclic aromatic compounds (S-HACs). S-HACs have been previously demonstrated to induce cellular stress in mammalian cells. This thesis aims to determine if S-HACs can induce cellular stress in beta cells and, consequently, impair beta cell function, particularly insulin production. Rat pancreatic beta cells, INS-1Es, were treated with two commonly occurring S-HACs, BNT(2,3D) and DBT, at doses which reflect non-occupational exposure levels. Upon treatment, various functional assays and qPCR experiments were performed for examining glucose uptake, ROS production, cellular senescence, ER stress and intracellular insulin production. It was observed that both BNT(2,3D) and DBT significantly increased glucose uptake and ROS production in the beta cells and upregulated the mRNA expression of various ER stress markers. In addition, BNT(2,3D) also induced cellular senescence, likely through a p53-independent pathway. This suggests that S-HACs may induce oxidative stress and ER stress in exposed beta cells, and some S-HACs may cause irreversible cell cycle arrest in response to these cellular stresses. However, intracellular insulin content in the INS-1Es was not altered by exposure to either S-HAC, suggesting that S-HACs may not impair insulin production. Nevertheless, the significant accumulation of ROS in S-HAC-exposed beta cells and the subsequent induction of cellular senescence by some S-HACs may alter other important beta cell functions, including mitochondrial function and insulin secretion, which could lead to the development of T2D; suggesting the potential for S-HACs to be novel beta cell toxicants. / Thesis / Master of Science (MSc)

Dietary soy isoflavones have been shown to ameliorate insulin resistance and Type 2 diabetes. However, many in vitro studies used supra-physiological concentrations of individual isoflavones that make it difficult to interpret the results as potential mechanisms in vivo. Since the insulin-sensitizing effects of thiazolidinediones, anti-diabetic drugs, have been shown to be mediated through activation of peroxisome proliferators-activated receptor gamma (PPARγ), the key transcription factor for adipocyte differentiation, we examined the effects of the two main soy isoflavones genistein and daidzein either as individual compound or combined on adipocyte differentiation and PPARγ expression, as well as whether the Wnt/β-catenin signaling pathway is the underlying molecular mechanism. In 3T3-L1 cells, genistein and daidzein significantly enhanced adipocyte differentiation. Similarly the expression of PPARγ increased particularly at 20 µmol/L. The stimulatory effect is greater when the two isoflavones are combined, indicating a synergistic effect. Genistein and daidzein also increased the relative abundance of insulin-responsive glucose transporter 4 (GLUT4) mRNA with a greater effect when combined. Wnt10b expression was not affected by soy isoflavones treatments, while Wnt5b expression was only increased by the combination of genistein and daidzein. Our results suggest, that the combination of soy isoflavones has a greater effect in increasing the newly formation of adipocytes that are highly insulin-sensitive via an increase in PPARγ expression as well as increasing the expression of GLUT4. However, genistein and daidzein actions on Wnt signaling remain unclear. These data further support the epidemiological findings for the beneficial effect of soy consumption on insulin sensitivity.

In the U.S., diabetes mellitus cases have been increasing, from 25 million in 2010 to 29 million in 2012. Healthy People 2020, the U.S. National Health Agenda, has established specific goals and objectives for diabetes. In the U.S., prevalence of pre-diabetes and diabetes for adult Hispanics was 38% and 12%, respectively, in 2012. The total estimated diabetes cost in the U.S. has been increasing, from $176 billion in 2007 to $245 billion in 2012. The current study had two research hypotheses; the formative phase was expected to demonstrate a need for a community-based Type 2 Diabetes Mellitus (T2DM) self-management intervention for Spanish-speaking Hispanics. Random Control Trial (RTC) was expected to demonstrate the potential impact in preventing and managing T2DM. Methods. A community-based lifestyle education curriculum was translated into Spanish, and adapted to Hispanic culture. This study includes three phases: 1) a formative phase; 2) a two-group pilot RCT with Hispanic Living with Diabetes (HBLD) and a delayed treatment condition; and 3) post-HBLD focus groups held with three participating groups of HBLD. Results. Of 60 participants screened in the formative phase, 62% had A1c > 5.7%, and 75% did not have medical insurance. Of 6 participants who completed the pilot, A1c decreased for all six participants. Of 67 participants screened in phase 2, 61% had A1c > 5.7%. Of 30 HBLD participants in the RCT, baseline versus 3-month mean A1c increased 0.2 for the delayed control group (n = 10) and did not experience any change for the intervention group (n = 11). The difference in A1c change from baseline to follow up between treatment groups was not statistically significant (Kruskal Wallis, p < 0.05). Diabetes knowledge and SCT variables change from baseline to follow-up between groups were not statistically significant. Major themes identified in focus group discussions included barriers to access to health and nutrition services, the value of having a Spanish-speaking Hispanic as a health educator, and barriers to recruiting community members as promotoras. Implications. HBLD has potential to reduce complications of diabetes among Hispanic participants by providing education to those who may not otherwise have access to it. / Ph. D.

STUDY 1 Aim: To compare the effects of Roux-en-Y gastric bypass (RYGB) and laparoscopic adjustable gastric banding (LAGB) on changes in bone mineral density (BMD), weight loss and blood biomarkers related to bone turnover, hormonal, and nutrient status. Subjects: Nine bariatric surgery patients. Methods: Patients had a DXA bone scan and fasting blood draw at baseline, three, and six months following surgery. Results: RYGB patients had greater weight loss vs. LAGB at both three (mean loss: 19 vs. 9%) and six months (26 vs. 11%), p<0.01. RYGB patients lost an average of 7% hip BMD at six months. Hip BMD loss at six months was correlated to decreased leptin (r=0.88) and increased adiponectin (r=-0.82), p<0.05. Bone turnover was indicated by elevated serum bone biomarkers after surgery. Conclusions: Research with larger sample sizes is warranted to better evaluate potential implications for late-life osteoporosis risk following bariatric surgery. STUDY 2 Aim: To determine repeatability for IMAT and muscle density, to evaluate the distribution of foreleg muscle and fat indices measured by pQCT and to determine predictors of muscle density and type-2 diabetes risk. Subjects: 82 women with varying BMI and physical activity levels. Methods: Subjects had DXA and pQCT bone scans, a fasting blood draw, and completed a 4-day physical activity record. Results: Fat and muscle distribution in the foreleg was highly correlated to total and central body adiposity. The pQCT device reliably measured muscle density (CV=0.8%), thus justifying use as surrogates for IMAT. Muscle density was positively related to physical activity (r=0.29; p<0.05) and negatively associated with markers of fat distribution and risk for type-2 diabetes [HOMA-IR (r=-0.44, p<0.01)]. Conclusions: Further research is necessary to determine whether specific fat or muscle depots can be targeted through exercise training to help with the prevention and treatment of obesity or type-2 diabetes. / Ph. D.

In chapter 1, a comprehensive meta-analysis is conducted to synthesize the effectiveness, cost, and cost-effectiveness of lifestyle diabetes prevention interventions and compare effects by intervention delivery agent and channel. Sixty-nine studies meet inclusion criteria. The results show that participants receiving intervention with nutrition education experienced a reduction of 2.07 kg (95% CI: 1.52 to 2.62; p<0.001; 95% CI: 88.61% to 92.87%) in weight at 12 months with effect sizes over time ranging from small (0.17, 95% CI: 0.04 to 0.30; p=0.012; 95% CI: 80.42% to 91.14%) to medium (0.65, 95% CI: 0.49 to 0.82; p<0.001; 95% CI: 98.52% to 98.94). In sum, lifestyle interventions are effective in reducing body weight and glucose-related outcomes. Dietitian-delivered interventions achieve greater weight reduction compared to those delivered by other personnel. In chapter 2, this study attempts to examine the effects of household relative deprivation on children's health outcomes. A modified household production model is developed with energy intake, energy expenditure and a composite good as main inputs in the health production. A two-stage Stackelberg game facilitates the need to model the parent-child interaction which follows similar structure as You and Davis (2011). We use three measurements of relative deprivation based on per capita household income and four reference groups based on combinations of geographic and demographic characteristics. The results show that relative deprivation is negatively associated with child health. In chapter 3, we define "process benefits" as the direct effect on utility from engaging in an activity and examine how "process benefits" associated with food activities, both uptake and duration, are related to factors such as socio-economic status and demographics. A household production model is utilized to demonstrate the vital role of process benefits in home food production and the implications it will have for nutrition based policies targeting resources. The results display that the process benefits are associated with some demographic characteristics. This implies that shortfalls in food activities are not simply a matter of technology or resource shortfalls, but also reflect disutility associated from these activities which in turn will attenuate the impact of policies design to merely address resource shortfalls. / Ph. D.

Type 2 diabetes affects more than one-quarter of older adults in the United States. Many older adults manage type 2 diabetes (T2D) in the context of marriage, although few studies have acknowledged the effect the illness has on marital quality. The current study examined how the presence of T2D in later life relates to marital quality, and how positive health behaviors--diet, physical activity, and sleep--can moderate the relationship between T2D and marital quality. Data from the 1,200 married older adults in the Life and Family Legacies study were used to estimate moderation models using structural equation modeling in Mplus. Results indicated that T2D is associated with declines in marital quality. In addition, lower glycemic diets moderate the association such that healthy diets (higher intake of low glycemic indexed foods) buffer the impact on T2D on marital quality. These findings suggest T2D effects social relationships, and that positive health behaviors, especially healthy diets, can help buffer the negative association between T2D and marital quality. These results have implication for health care providers who can view patients' diabetes management in the context of their health behaviors and social relationships to best provide resources for management.

Yes / Smoking increases the risk of developing type 2 diabetes. However, several population studies also show a higher risk in people 3–5 years after smoking cessation than in continuing smokers. After 10–12 years the risk equates to that of never-smokers. Small cohort studies suggest diabetes control deteriorates temporarily during the first year after quitting. We examined whether or not quitting smoking was associated with altered diabetes control in a population study, for how long this association persisted, and whether or not this association was mediated by weight change. Methods We did a retrospective cohort study (Jan 1, 2005, to Dec 31, 2010) of adult smokers with type 2 diabetes using The Health Improvement Network (THIN), a large UK primary care database. We developed adjusted multilevel regression models to investigate the association between a quit event, smoking abstinence duration, change in HbA1c, and the mediating effect of weight change. Findings 10 692 adult smokers with type 2 diabetes were included. 3131 (29%) quit smoking and remained abstinent for at least 1 year. After adjustment for potential confounders, HbA1c increased by 0·21% (95% CI 0·17–0·25; p<0·001; [2·34 mmol/mol (95% CI 1·91–2·77)]) within the first year after quitting. HbA1c decreased as abstinence continued and became comparable to that of continual smokers after 3 years. This increase in HbA1c was not mediated by weight change. Interpretation In type 2 diabetes, smoking cessation is associated with deterioration in glycaemic control that lasts for 3 years and is unrelated to weight gain. At a population level, this temporary rise could increase microvascular complications.

Yes / To explore the perception of healthcare workers (HCWs) on diabetic foot ulcers (DFU) and foot care in Rotuma, Fiji. Using a qualitative study design, two focus group discussions (FGDs) were conducted among HCWs. A semistructured open-ended questionnaire was used to guide the discussion session. Each FGD was audiorecorded and was transcribed. The transcriptions were then manually analysed using thematic analysis. Rotuma hospital, Fiji. HCWs who were working in Rotuma hospital for at least a year and were involved in clinical foot care of type 2 diabetes mellitus patients were included. There were five main themes, namely, depth of knowledge, quality of care in practice, factors of influence on practice, lack of resources and capacity building. Participants had superficial knowledge that showed lack of in-depth scientific knowledge. A lack of staffing in the clinics affected the delivery of service. Additionally, patients defaulting clinics, late presentations with DFU and traditional medicine also affected the quality of healthcare service in clinics. There was also a need for a multidisciplinary team to prevent and manage DFU. HCWs mostly advised on glycaemic control and ignored offering foot care advice in clinics due mainly to the lack of sound knowledge on foot care. There was also a lack of resources, infrastructure, space and professional development opportunities, which negatively impacted how HCWs deliver foot care services to patients. HCWs lack significant in-depth knowledge on DFU and foot care. In addition, these are the availability of traditional medicine that delays presentations to hospital, further reducing the quality of services. HCWs need to keep their knowledge and skills updated through regular in-service training on foot care. Resources, infrastructure and supply chains need to be maintained by those in power to ensure HCWs deliver quality foot care services.

Pre-existing diabetes, type 1 or type 2 diabetes, can be a challenge to manage during pregnancy. Due to the increased fetal and obstetrical risks from hyperglycemia, women are advised to keep blood glucose as close to normal as possible. Diabetes distress is the negative emotional experience of managing diabetes, with prevalence between 20-50% in non-pregnant adults with diabetes. As diabetes distress during pregnancy has not been well studied, the purpose of this study was to use a sequential explanatory mixed methods approach to understand the extent and impact of diabetes distress. This was achieved by first conducting a cross-sectional quantitative study with 76 women pre-existing diabetes. Diabetes distress was measured with the Problem Area in Diabetes (PAID) Scale and a score of 40 or higher indicated high diabetes distress. Women with both types of diabetes and high and low PAID scores were recruited to the second strand, which was an interpretive description qualitative study. Semistructured interviews were conducted with 18 women discuss their experiences of diabetes distress and managing diabetes in pregnancy. In the mixed methods analysis, it was observed that while diabetes distress was seen in 22.4% of women, the majority of women who took part in the qualitative interviews described themes of diabetes distress whether they had a high or low PAID distress score. Current diabetes distress tools are not validated for pregnancy, and qualitative findings indicate that diabetes distress during pregnancy is uniquely defined by worries for the baby. Development of a pregnancy-specific diabetes distress tool for integrated screening during pregnancy would be beneficial to better capture distress rates in this population. The counterpart to the qualitative findings of diabetes distress were findings of resiliency demonstrated by the participants. Further research is needed to better understand appropriate interventions to increase resiliency in pregnancy to mitigate diabetes distress. / Thesis / Doctor of Philosophy (PhD) / Women with type 1 and type 2 diabetes require intensive blood sugar control while they are pregnant in order to have a healthy pregnancy. While it is known that diabetes during pregnancy can be challenging emotionally, there is limited information about how diabetes distress affects this group. The aim of this thesis is to understand how many women report diabetes distress during pregnancy and how they perceive diabetes distress. This thesis includes a synthesis of the literature on mental health and psychosocial well-being, a study that administered surveys at one time during pregnancy, a study that used interviews to ask the same women about their experience of pregnancy with diabetes, and a study that mixed the survey and interview results. The results illuminate the extent to which diabetes distress affects women during pregnancy, informing future research that will help better screen for diabetes distress and improve clinical care during pregnancy.

<p dir="ltr">Diabetes has become an international health crisis with type 2 diabetes composing the majority of cases. Along with a variety of other systemic effects, type 2 diabetes increases fracture risk. This aspect of type 2 diabetes has become a topic of interest in preclinical research and has been investigated using rodent models of type 2 diabetes. Of these models, the Yellow Kuo Kondo (KK-A^y) mouse model has shown promise as an obese model of type 2 diabetes. In the KK-A^y model, mice heterozygous for a mutation in the agouti gene (A^y) are treated as an obese model of type 2 diabetes. Those that are homozygous (no mutation) are treated as non-diabetic, obese controls. While this model has been indicated to be non-diet dependent, recent data has revealed the efficacy of this model may be reliant on diet. Following approval from the Indiana University-Purdue University at Indianapolis School of Science Institutional Animal Care and Use Committee, mice of each sex and genotype were placed on separate diets. Half on a standard chow diet and the other half on a diet recommended by Jackson Laboratory for this strain. Animals were aged to 16 weeks of age with blood glucose and body weight monitored every other week. Animals were then sacrificed to collect whole blood, blood serum, the pancreas, bilateral tibiae, and bilateral femora. End-point metabolic impacts were assessed through hemoglobin A1c and serum insulin measures while skeletal measures were quantified using microcomputed tomography scanning and analysis. Through this research, it was determined diet did have a significant impact on the skeletal and metabolic phenotype associated with type 2 diabetes in the KK-A^ymodel. </p>