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.

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.

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.

Introduktion: Diabetes typ 2 (DT2) är en allvarlig sjukdom som innebär risk för svåra komplikationer. Sjukdomen är ärftlig men uppkommer också till följd av ohälsosamma levnadsvanor och prevalensen ökar markant i världen. Socialstyrelsen rekommenderar att stöd till förändring av levnadsvanor och fysisk aktivitet genom grupputbildning ska ingå i behandlingen men trots detta erbjuds det i alldeles för liten utsträckning i landet. Till följd av detta har ett nytt arbetssätt för grupputbildning utvecklats för att öka tillämpningen i primärvården. Syfte: Syftet med studien är att utvärdera hur en multidisciplinär gruppintervention för personer med DT2 med fokus på livsstilsförändring och fysisk aktivitet (FA) påverkar vikt, hälsorelaterad livskvalitet och grad av FA. Metod: Detta är en longitudinell prospektiv studie. Data som analyserats är hämtad från ett kliniskt utvecklingsprojekt vid namn Tillsammans. Deltagarna (N=34) genomförde en gruppbaserad utbildning med fokus på levnadsvanor. Data samlades in vid baslinjen och efter sex månader. Deskriptiv analys och Wilcoxons teckenrangtest användes för bearbetning av data. Resultat: Resultatet visade statistiskt signifikant förbättring av vikt och hälsorelaterad livskvalitet. Ingen signifikant förbättring sågs för FA. Antalet deltagare som uppnådde rekommendationerna för FA förändrades inte efter interventionen. Skillnader observerades mellan kön och åldersgrupper i alla variabler men testades inte statistiskt.  Konklusion: Denna studie visade att den multidisciplinära gruppinterventionen gav stöd till förändring av levnadsvanor. Vidare observerades trender som tyder på att kön och ålder eventuellt kan påverkas olika. Få deltagare och stort bortfall försvårade utvärderingen av gruppintervention

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. / Evaluation of programs is a vital part in health economics for it is important in understanding the effect and limitation of a program from an economic perspective. Three applications are included in this dissertation. The first application is to synthesize the overall effectiveness of diabetes prevention program including nutrition education; the second application is to evaluate if there is a negative association between relative deprivation and children’s health outcomes; the third one is to explain the small effect of nutrition policy, such as SNAP. Type 2 diabetes (T2D) has increased significantly worldwide, leading to substantial increases in total economic costs in the US. A proliferation of studies have attempted to translate lifestyle interventions into clinical and community practice in an attempt to halt this growing public health epidemic. Therefore, there is a need to investigate the effectiveness of interventions including nutrition education for diabetes prevention. The results show that diabetes prevention program with nutrition education is effective in reducing body weight and glucose-related outcomes. China has reached the fastest rate of growth in economy since the implementation of reform and become the world’s second largest economy. However, improvement in health fails to accompany the massive growth in material living standards for the Chinese population. This observation prompts us to investigate the relative deprivation hypothesis. The results show that children who are more relatively deprived have poor health outcomes. Food assistance programs, e.g., Supplemental Nutrition Assistance Program (SNAP), have been developed to improve people’s health. However, the nutrition level recommended by those programs are still not met for the targeted population. The results show that respondents who enjoy cooking spend more time on activities related to food production, such as food preparation, presentation and clean up. And the small effect of nutrition policies is due to the disutility from the process of food production.

No / Cardiovascular disease is the principal cause of death in patients with type 2 diabetes (T2DM). Exposure of the vasculature to metabolic disturbances leaves a persistent imprint on vascular walls, and specifically on smooth muscle cells (SMC) that favours their dysfunction and potentially underlies macrovascular complications of T2DM. Current diabetes therapies and continued development of newer treatments has led to the ability to achieve more efficient glycaemic control. There is also some evidence to suggest that some of these treatments may exert favourable pleiotropic effects, some of which may be at the level of SMC. However, emerging interest in epigenetic markers as determinants of vascular disease, and a putative link with diabetes, opens the possibility for new avenues to develop robust and specific new therapies. These will likely need to target cell-specific epigenetic changes such as effectors of DNA histone modifications that promote or inhibit gene transcription, and/or microRNAs capable of regulating entire cellular pathways through target gene repression. The growing epidemic of T2DM worldwide, and its attendant cardiovascular mortality, dictates a need for novel therapies and personalised approaches to ameliorate vascular complications in this vulnerable population.

Yes / Type 2 diabetes (T2DM) confers increased risk of endothelial dysfunction, coronary heart disease, and vulnerability to vein graft failure after bypass grafting, despite glycaemic control. This study explored the concept that endothelial cells (EC) cultured from T2DM and nondiabetic (ND) patients are phenotypically and functionally distinct. Cultured human saphenous vein- (SV-) EC were compared between T2DM and ND patients in parallel. Proliferation, migration, and in vitro angiogenesis assays were performed; western blotting was used to quantify phosphorylation of Akt, ERK, and eNOS. The ability of diabetic stimuli (hyperglycaemia, TNF-α, and palmitate) to modulate angiogenic potential of ND-EC was also explored. T2DM-EC displayed reduced migration (~30%) and angiogenesis (~40%) compared with ND-EC and a modest, nonsignificant trend to reduced proliferation. Significant inhibition of Akt and eNOS, but not ERK phosphorylation, was observed in T2DM cells. Hyperglycaemia did not modify ND-EC function, but TNF-α and palmitate significantly reduced angiogenic capacity (by 27% and 43%, resp.), effects mimicked by Akt inhibition. Aberrancies of EC function may help to explain the increased risk of SV graft failure in T2DM patients. This study highlights the importance of other potentially contributing factors in addition to hyperglycaemia that may inflict injury and long-term dysfunction to the homeostatic capacity of the endothelium.

Yes / Type 2 diabetes (T2DM) promotes premature atherosclerosis and inferior prognosis after arterial reconstruction. Vascular smooth muscle cells (SMC) respond to patho/physiological stimuli, switching between quiescent contractile and activated synthetic phenotypes under the control of microRNAs (miRs) that regulate multiple genes critical to SMC plasticity. The importance of miRs to SMC function specifically in T2DM is unknown. This study was performed to evaluate phenotype and function in SMC cultured from non-diabetic and T2DM patients, to explore any aberrancies and investigate underlying mechanisms. Saphenous vein SMC cultured from T2DM patients (T2DM-SMC) exhibited increased spread cell area, disorganised cytoskeleton and impaired proliferation relative to cells from non-diabetic patients (ND-SMC), accompanied by a persistent, selective up-regulation of miR-143 and miR-145. Transfection of premiR-143/145 into ND-SMC induced morphological and functional characteristics similar to native T2DM-SMC; modulating miR-143/145 targets Kruppel-like factor 4, alpha smooth muscle actin and myosin VI. Conversely, transfection of antimiR-143/145 into T2DM-SMC conferred characteristics of the ND phenotype. Exposure of ND-SMC to transforming growth factor beta (TGFβ) induced a diabetes-like phenotype; elevated miR-143/145, increased cell area and reduced proliferation. Furthermore, these effects were dependent on miR-143/145. In conclusion, aberrant expression of miR-143/145 induces a distinct saphenous vein SMC phenotype that may contribute to vascular complications in patients with T2DM, and is potentially amenable to therapeutic manipulation.

Yes / Background/purpose Coronary heart disease is the leading cause of morbidity in patients with type 2 diabetes mellitus (T2DM), frequently resulting in a requirement for coronary revascularization using the internal mammary artery (IMA) or saphenous vein (SV). Patency rates of SV grafts are inferior to IMA and further impaired by T2DM whilst IMA patencies appear similar in both populations. Smooth muscle cells (SMC) play a pivotal role in graft integration; we therefore examined the phenotype and proliferative function of IMA- and SV-SMC isolated from non-diabetic (ND) patients or those diagnosed with T2DM. Methods/materials SMC were cultured from fragments of SV or IMA. Morphology was analyzed under light microscopy (spread cell area measurements) and confocal microscopy (F-actin staining). Proliferation was analyzed by cell counting. Levels of RhoA mRNA, protein and activity were measured by real-time RT-PCR, western blotting and G-LISA respectively. Results IMA-SMC from T2DM and ND patients were indistinguishable in both morphology and function. By comparison, SV-SMC from T2DM patients exhibited significantly larger spread cell areas (1.5-fold increase, P < 0.05), truncated F-actin fibers and reduced proliferation (33% reduction, P < 0.05). Furthermore, lower expression and activity of RhoA were observed in SV-SMC of T2DM patients (37% reduction in expression, P < 0.05 and 43% reduction in activity, P < 0.01). Conclusions IMA-SMC appear impervious to phenotypic modulation by T2DM. In contrast, SV-SMC from T2DM patients exhibit phenotypic and functional changes accompanied by reduced RhoA activity. These aberrancies may be epigenetic in nature, compromising SMC plasticity and SV graft adaptation in T2DM patients.

Yes / Type 2 diabetes mellitus prevalence is growing globally, and the leading cause of mortality in these patients is cardiovascular disease. Epigenetic mechanisms such as microRNAs (miRs) and DNA methylation may contribute to complications of type 2 diabetes mellitus. We discovered an aberrant type 2 diabetes mellitus–smooth muscle cell phenotype driven by persistent up-regulation of miR-145. This study aimed to determine whether elevated expression was due to changes in methylation at the miR-145 promoter. Smooth muscle cells were cultured from saphenous veins of 22 non-diabetic and 22 type 2 diabetes mellitus donors. DNA was extracted, bisulphite treated and pyrosequencing used to interrogate methylation at 11 CpG sites within the miR-145 promoter. Inter-patient variation was high irrespective of type 2 diabetes mellitus. Differential methylation trends were apparent between non-diabetic and type 2 diabetes mellitus–smooth muscle cells at most sites but were not statistically significant. Methylation at CpGs −112 and −106 was consistently lower than all other sites explored in non-diabetic and type 2 diabetes mellitus–smooth muscle cells. Finally, miR-145 expression per se was not correlated with methylation levels observed at any site. The persistent up-regulation of miR- 145 observed in type 2 diabetes mellitus–smooth muscle cells is not related to methylation at the miR-145 promoter. Crucially, miR-145 methylation is highly variable between patients, serving as a cautionary note for future studies of this region in primary human cell types.