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<p>Type 1 diabetes mellitus (T1DM) is a disease defined by its complications as much as its central pathology. One such complication, diabetic myopathy, has received more attention in recent years as it has become clear that by maintaining a healthy skeletal muscle mass, diabetic individuals are more likely to maintain metabolic control and avoid the health consequences associated with hyperglycemia. While only a limited number of studies have been performed on diabetic human skeletal muscle, the research clearly indicates that a loss of muscular strength and alterations in muscle phenotype are a result of T1DM, occurring within weeks of disease inception. Studies employing rodent models of T1DM have identified several key changes underlying the loss of contractile capacity and the changes to muscle phenotype. The research to date, however, has yet to thoroughly elucidate the mechanisms underlying diabetic myopathy. The goal of the following studies is to gain a more thorough understanding of the effects of T1DM on skeletal muscle contractile capacity, morphology, and regenerative capacity using the C57BL/6J-<em>Ins2^Akita</em> (<em>Ins2</em>^WT/C96Y) diabetic mouse model. Given the crucial role of muscle repair in maintaining a healthy muscle mass, any deficit observed here could have important implications in the pathophysiology of diabetic myopathy. The results of the following studies indicate that the <em>Ins2</em>^WT/C96Y mouse undergoes a loss of glycolytic muscle mass and other morphological/phenotypic alterations concomitant with loss of peak contractile force. Furthermore, the regenerative capacity of the muscle following injury is impaired in glycolytic muscle groups, particularly the tibialis anterior (TA). This impairment in regeneration can be, at least partly, attributed to chronic elevation in plasminogen activator inhibitor-1 (PAI-1). Pharmacological inhibition of this hormone improves regeneration of the TA in the <em>Ins2</em>^WT/C96Y mouse. These data have improved our mechanistic understanding of diabetic myopathy and have clinical implications for the treatment of T1DM.</p> / Doctor of Philosophy (PhD)

Type 1 diabetes (T1D) is a chronic disease that is due to the dysregulation of glucose in the blood when insulin is not made endogenously. Patients rely on a combination of exogenic insulin, medications, blood glucose monitoring, and healthy lifestyle activities such as dietary control and exercise to manage their blood glucose levels. T1D typically begins its onset during childhood or adolescence, where it may also affect the development of executive function (EF) processes which are also relevant for self-regulation, or goal-directed behavior. This in turn may affect individuals’ adherence to their T1D management regimens, which can result in severe short- and long-term complications. Despite evidence for the plasticity of EF during childhood, previous research has not frequently focused on EF or self-regulation (SR) as a possible mechanism for improving health outcomes in adolescents with T1D. This study focused on the dosage of EF training and its possible effects on both cognitive and health outcomes for 47 adolescents (M= 15.4, SD =1.45) with T1D undergoing a larger adherence intervention. EF was measured by the Digit Span and Go/No-Go tests, while composite measures of T1D treatment adherence were aggregated via separate parent and adolescent reports. It was hypothesized that both cognitive measures and treatment adherence would have a dose-dependent relationship with n-back training. However, no association was found between training dosage and EF outcomes or treatment adherence. The study’s limitations include a relatively small sample size along with low participant compliance for the EF training. It also might be that the relationship between EF, SR, and health behaviors is more nuanced than previously suggested and that there are a variety of reasons why dosage of training was not linked to differential outcomes. As such, further investigation is required to better understand this relationship in the search for effective interventions for health behavior. / M.S. / Adolescents with Type 1 Diabetes often demonstrate difficulty following their diabetes management plans. One potential reason for these challenges may be that their self-regulation (the ability to intentionally direct their behavior towards a goal) is still developing. This study examined whether there was a dose-response relationship between a cognitive intervention aimed at increasing cognition/self-regulation as well as adherence to diabetes management regimens. The sample included 47 adolescents whose mean age was 15 years. Overall, no effect of dosage of cognitive training was observed on the adolescents' cognitive performance or diabetes management adherence. Reasons for this finding include the study's small sample size, low participation in the cognitive training, or a more nuanced relationship between self-regulation and health behavior.

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.

Cell therapy is a novel potential approach to treat many diseases including diabetes. Embryonic stem cells have been examined in various diabetic and non-diabetic heart studies. However, the role of pancreas transcription factor 1 alpha (ptfla) over expressing embryonic stem (ES) cells has not been defined. We hypothesize that transplanted over expressing ptfla-ES cells in streptozotocin (STZ) induced diabetic mice will attenuate cardiac hypertrophy, fibrosis, and improve cardiac function. In this investigation we divided C57/bl6 mice into three groups: Control, STZ, and STZ + ptflaES cells. Diabetes was induced with STZ (lO0mg/kg, body weight), with two separate injections on day 1 (D1) and D2. Following STZ injections, mice were transplanted with 1.2 million ptfla-ES cells in three days. Control group received normal saline. After injections, animals were examined for glucose levels, cardiac hypertrophy, fibrosis, and heart function. Our data shows that glucose levels were significantly increased following STZ injections, suggesting diabetes, and this increase was reversed with transplanted ptfl a-ES cell. Our H&E qualitative data suggest that there was increase in cardiac hypertrophy in STZ-induced diabetic animals compared with control. Moreover, Massan's trichrome staining shows increased amount of cardiac fibrosis in STZ-induced diabetic animals compared with control. This data suggests that animals have developed diabetic cardiomyopathy. Interestingly, the increased cardiac hypertrophy and fibrosis was attenuated in the animals transplanted with ptfl a-ES cells. Furthermore, cardiac function examined by echocardiography was reduced in the STZ treated animals which was reversed following ptfla-ES cell treatment. In conclusion, our data suggests that

Children diagnosed with Type 1 diabetes face lifetime issues that will affect their health-related quality of life (HRQoL). These challenges require varied coping skills to manage the disease and a commitment to find ways to increase HRQoL. It was proposed that children’s general coping styles would be mediators in both the relation of family environment and children’s health-related quality of life and the relation of parental perceived social support and children’s health-related quality of life in children aged 8-16 with Type 1 diabetes. Age was also proposed to be a moderator in the relation of children’s coping to their health-related quality of life. Children aged 8 to 16 and their primary caregivers (N = 56) were recruited to participate in the study at a university hospital tertiary care clinic. Children completed the Pediatric Quality of Life Inventory 3.0 Diabetes Module for children and adolescents (PedsQL 3.0) and the Children’s Coping Strategies Checklist-Revision 1. Primary caregivers completed the PedsQL 3.0 for parents, the Family Environment Scale and the Multidimensional Scale of Perceived Social Support. Regression analyses were used to identify a model that explained the contribution of each factor to predict HRQoL. It was hypothesized that children’s active, distraction, and support-seeking general coping strategies would be mediators in the relation of family environment and parental perceived social support to children’s health-related quality of life and that children’s general avoidant coping strategies would not mediate either the relation of family environment or parental perceived social support to children’s health-related quality of life. Although children’s active, distraction, and support-seeking coping strategies were not found to mediate the relation of family environment to children’s health-related quality of life or the relation of parental perceive social support to health-related quality of life, children’s avoidant coping strategies were found to be a mediator in the relation of family environment to children’s health-related quality of life and in the relation of parental perceived social support to health-related quality of life. It was also hypothesized that children’s age would moderate the relation of children’s active, distraction, and support-seeking coping strategies to children’s health-related quality of life. Age moderated the relation of avoidant coping to HRQoL. Avoidant coping was negatively associated with HRQoL for the older children but the association was not significant for younger children. To facilitate a better health-related quality of life for children with Type 1 diabetes, therapists and healthcare professionals should identify ways to help parents feel more supported as they care for and create a more cohesive and low conflict family environment, which contributes to their children’s health-related quality of life. Additionally, therapists should work with children and their parents to increase children’s use of active, distraction, and support-seeking coping strategies, which are related to more positive outcomes compared to children’s use of avoidant coping strategies, which are related to less positive outcomes. / Ph. D. / This research study explored social and emotional climate in families, perception of parents’ social support, and children’s coping as factors that contribute to the health-related quality of life (HRQoL) in children aged 8 to 16 with Type 1 diabetes. One of the main goals of treatment for children diagnosed with Type 1 diabetes is preventing nerve, heart, and blood vessel damage from occurring in adulthood. When children are diagnosed with Type 1 diabetes, they face a lifetime issues that will affect their HRQoL. These challenges require children to develop skills to help them process both the expected and unexpected emotions and thoughts that occur while managing the disease and a commitment to find ways to increase HRQoL over the span of their lives. It was hypothesized that children with better social and emotional family climates or environments and more parental perceived social support would be able to more effectively cope and that better coping would be associated with more health-related quality of life. Effective forms of coping included three different strategies: active (e. g., use of positive restructuring of thoughts), distraction (e. g., use of physical release of emotion), and support-seeking (e. g., seeking support for managing feelings). Avoidant coping was also examined and included use of actions such as wishful thinking. Of note, the children’s coping measure used identified use general coping strategies and was not diabetes specific. Children with connected, expressive, and low conflict family climates and with parents who perceived themselves being supported more were lower in avoidant coping, which was related to more HRQoL for the children. How coping was associated with HRQoL was also predicted to be different when looking at older versus younger children. As children aged, their use of avoidant coping strategies increased and more avoidant coping was related to less HRQoL for older children but not for younger children. To facilitate a better health-related quality of life for children with Type 1 diabetes, therapists and healthcare professionals should identify ways to help parents feel more supported as they care for and create a more cohesive and low conflict family environment, which can contribute to their children’s health-related quality of life. Additionally, therapists should work with children and their parents to decrease children’s use of avoidant coping strategies, which are related to less positive outcomes.