Human enteroviruses (HEVs), particularly Coxsackie B viruses (CVBs), might trigger the onset of type 1 diabetes (T1D), either by direct infection of the insulin-producing beta-cells or by an indirect inflammatory response. The overall aim of this thesis was to study the tropism of HEVs in isolated human pancreatic cell clusters in vitro including virus effects on islet function, gene-expression and ultrastructure. Furthermore, the expression of the major CVB-receptor, CAR, was investigated in pancreatic tissue from T1D-related subjects and CVB-infected islets. Also, tissues and isolated islets from two adult organ-donors who died close to disease onset were studied.The results showed that beta-cells were destroyed through lytic infections with different strains of CVBs and that islets function did not depend on replication per se but on the degree of islet destruction. Virus particles were observed in beta-cells in association with insulin granules, however no virus replication or particles could be observed in the exocrine cell clusters, as opposed to in mice models. The virus-infected islets had a decreased expression of insulin mRNA and CAR mRNA/protein, possibly reflecting virus-killed beta-cells. Infected beta-cells contained a high number of insulin granules, which might indicate an impaired function.The in vivo studies showed presence of virus proteins in the islets of both donors who died close to onset of T1D and elevated expression of innate immunity genes, potentially indicating viral infection, but direct evidence is lacking. Both donors were immune-reactive for insulin but the isolated islets had an impaired or completely lacking glucose response. Ultrastructural analysis showed both damaged beta-cells and normal-looking beta-cells, indicating that the latter might still have the potential to function but were blocked. CAR-expression was significantly increased in T1D-related subjects which might indicate tissue damage and/or inflammation in these subjects.To conclude, these results showed that CVBs could infect human primary beta-cells, likely by binding to CAR and lead to functional abnormalities, indicating that they could cause T1D in vivo. Exocrine cells were not permissive to CVB, which raises the question if mice-models should be used to study human pancreatitis. Also, unique materials from two T1D organ-donors were described.

This thesis is an investigation of the factors that impact psychological adjustment and metabolic control in children and adolescents with type 1 diabetes. Studies suggest that aspects of the family environment (stressful life events, family functioning and parent mental health) and child characteristics such as age, sex, executive functioning and hopeful thinking impact psychological adjustment and metabolic control. There is also evidence that coping processes mediate these associations. The purpose of this study was to 1) explore and identify developmental differences in coping processes in a sample of children with T1D, 2) identify the family system characteristics that are associated with child coping processes and psychological adjustment, and 3) identify the family and child characteristics that impact metabolic control. Survey data were collected through convenience sampling from an outpatient hospital clinic. Children aged 8 to 17 completed self-reports of hopeful thinking and illness-related coping style. Caregivers provided demographic information and completed questionnaires on their child’s physical health, stressful life events, mental health, family functioning, as well as the child’s initiative, emotional control, and psychological adjustment. Ratings of child metabolic control (HbA1C) were also retrieved from hospital patient records. A predictive model examining direct and indirect contributions of the family environment and coping variables toward child adjustment and metabolic control was tested. Age and sex differences in children’s coping style were identified. Family functioning and parent mental health were found to predict child psychological adjustment. Coping processes, including avoidant coping, coping efficacy and executive functioning mediated relations between family functioning and child adjustment. Results provided partial support for a mediational model of family system characteristics that influence psychological adjustment in the sample. Family functioning and parent mental health had a direct impact on children’s psychological adjustment, as well as indirect effects on adjustment through coping processes (i.e., coping style, coping efficacy, initiative and emotional control). Child age was found to moderate some paths in the proposed model. Clinical and research implications are discussed.

Introduction: Women possess characteristics and experiences unique and different from men. Menstruation, pregnancy, puberty and menopause may present challenges for self-management, a prerequisite for those living with Type 1 diabetes mellitus (T1DM). The meaning and experiences of self-management have not been adequately explored from a young woman’s perspective within the diabetes literature. Purpose of the Study: Blood glucose and glycosylated hemoglobin (HbA1c) values are keys for determining success in self-management among individuals living with T1DM; however, the values may enable feelings of vulnerability and worthlessness in individuals living with T1DM. Through learning about the experiences of young women, it was hoped that the meaning of self-management would be uncovered. The research question was: What are the experiences of self-management among young women with Type 1 diabetes mellitus? Methods and Methodology: Descriptive phenomenology was used to uncover the experiences of self-management. Unstructured interviews with nine young women aged 22-30 years were conducted to uncover their lived experience. Data collection and analysis followed the methodical structure outlined by van Manen (1997). Findings: Data analysis revealed five themes, and the essence of participants’ self-management experiences. Identified themes included: 1) elusiveness of control; 2) the dualism of technology; 3) forecasting and establishing routines; 4) dealing with the “ups and downs”; and, 5) interface with the health care team. The essence that emerged from the data was “being in balance”. Conclusions: Self-management encompassed the desire and need to be in balance with one’s life and blood glucose levels. Self-management was something that evolved over time, and grew in complexity as phases progressed; it was something participants were still trying to grasp. Individual attitudes, goals, and self-management strategies dominated participants’ discourse in describing their hope of achieving and sustaining balance in their day-to-day lives. / Thesis (Master, Nursing) -- Queen's University, 2012-01-24 18:35:33.911

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While carotenoids are essential for visual function, their potential role in diabetic retinopathy is not known. By providing carrot powder, this study examined carotenoid metabolism and visual function in Type 1 diabetes. Wistar rats (n=30) were assigned to diet either with or without carrot enrichment (15%, w/w) for 12 weeks. Type 1 diabetes was induced with streptozotocin at 3 weeks. Retinal function and anatomical integrity were assessed along with retinoid and carotenoid levels in the serum, liver, and retina. Loss of ERG oscillatory potentials, with normal histology indicated early stage retinopathy. Healthy animals fed carrot diet showed highest b-wave amplitudes; reflecting higher phototransduction. Diabetic animals fed carrot diet had the lowest b-wave amplitudes, reduced retinoids liver reserves, and highest α- and β-carotene, suggesting disturbance of conversion during diabetes. Consequently carrot powder at concentrations used by this study cannot be recommended for diabetic retinopathy.

The aim of the study was to explore the role of autonomy in participants’ self-management of exercise behaviours and the transfer of responsibility throughout adolescence. The design of this study used qualitative description with information collected and presented using a case study approach. Participants were five emerging adults (aged 18–24) with Type 1 diabetes for a minimum of one year who lived in Canterbury. Data was gathered through three sources: a semi-structured interview seeking self-reported exercise throughout adolescence, a set of questionnaires based on four instruments, and physical activity performed over a week as recorded by an activity monitor. All participants achieved autonomy for exercise, however participants achieved autonomy at different ages. Participants’ diabetes self-management and physical activity levels varied according to their stage of life and lifestyle. They received varying advice about exercise from health professionals. Participants sought to determine their own exercise choices during adolescence, leading them to obtain a driver licence to be independent of parental transport. Three of the five met current guidelines for physical activity levels, and another met recommendations by her clinician. Policy implications regarding healthcare advice and barriers to exercise for young people are discussed, as are limitations of the research and future avenues for research.

Transplantation of the islets of Langerhans is a promising technique for restoring the impairedinsulin production in brittle type 1 diabetics. The downside is that the patient will have to takeimmunosuppressant drugs in order to protect the islet cells from the immune system. Donorsare also sparse, making the quest of finding sufficient amounts of islets for transplantationhard. Encapsulation of the islets of Langerhans has been proposed as a means of protectingthe cells from the immune system taking away the need for immunosuppresives. The mostcommon encapsulation technique is extravascular capsules, which are categorized into micro-and macrocapsules. The microcapsules hold only one or a small set of islet whereas themacrocapsules hold a large quantity of islets.This thesis investigates the encapsulation impact on the beta-cells rapid insulin response torising plasma glucose levels. This was done by simulating the glucose-insulin system inMATLAB with included encapsulation of the islets. Two current macro-encapsulation set upswere used in the model, Beta-Air and ViaCyte devices, and they were compared against anormal case. The results showed that the Beta-Air device would not be able to restorenormoglycemia in a T1DM patient but rather showed a delay in insulin response, while theViaCyte device could mimic the normal case well.

Abstract Background: Patients diagnosed with Type 1 diabetes mellitus (T1DM) require insulin therapy. Although necessary, insulin therapy is associated with an immediate increase in Body Mass Index (BMI). Excessive increase in BMI may lead to obesity, which is associated with both short and long-term negative health outcomes. The objective of this study was to determine whether weight change in the six months after diagnosis in children and adolescents with T1DM is related to obesity status at age 18. Methods: Data from the Diabetes Education Resource for Children and Adolescents database was used for this study. This unique database combines extensive clinical information on each patient with virtually universal coverage. The study population comprised all children 2-18 years old diagnosed with T1DM by DER-CA endocrinologists in Manitoba between 1997 and 2012 (N=377). BMI z- scores calculated from measured height and weight were used to classify BMI group membership using the 2000 Centers for Disease Control growth charts. Regression models were used to assess the association between change in BMI z-score six months after diagnosis, and BMI z-score at last visit prior to transfer to adult care. The models controlled for BMI z-score at diagnosis, sex, pubertal status and length of follow up. Additional stratified analyses examined sub-groups within the sample, to determine whether the effects were different for children with different characteristics (e.g. sex and pubertal status at diagnosis). Results: At diagnosis, 9% of the study cohort was underweight, 68% normal weight, 15% overweight and 8% obese. Most, (91%) but not all patients gained weight in the six months after T1DM diagnosis and initiation of insulin therapy. The pattern of weight change differed by BMI group at diagnosis, sex, and pubertal status. At last visit, average BMI z-scores for all groups of patients were above zero, and varied less than BMI z-scores at diagnosis. Results of the multivariate analytic model (adjusted R2= 0.56) show that BMI z-score at diagnosis was most important, followed by female sex, change in BMI z-score in the six months after diagnosis, the interaction between BMI z-score at diagnosis and change in BMI z-score in the six months after diagnosis, and duration of follow up. Conclusion: Results of this study demonstrate that patients’ BMI group, sex, and pubertal status at diagnosis influenced the pattern of their BMI z-score change in the six months after diagnosis, and thereafter. Diabetic care teams may need to monitor not only the amount of weight change in the period after T1DM diagnosis, but also consider BMI at diagnosis.

While carotenoids are essential for visual function, their potential role in diabetic retinopathy is not known. By providing carrot powder, this study examined carotenoid metabolism and visual function in Type 1 diabetes. Wistar rats (n=30) were assigned to diet either with or without carrot enrichment (15%, w/w) for 12 weeks. Type 1 diabetes was induced with streptozotocin at 3 weeks. Retinal function and anatomical integrity were assessed along with retinoid and carotenoid levels in the serum, liver, and retina. Loss of ERG oscillatory potentials, with normal histology indicated early stage retinopathy. Healthy animals fed carrot diet showed highest b-wave amplitudes; reflecting higher phototransduction. Diabetic animals fed carrot diet had the lowest b-wave amplitudes, reduced retinoids liver reserves, and highest α- and β-carotene, suggesting disturbance of conversion during diabetes. Consequently carrot powder at concentrations used by this study cannot be recommended for diabetic retinopathy.

Elevated plasma lipids are risk factors for cardiovascular disease (CVD). In certain conditions plasma lipids are normal yet individuals experience increased morbidity. Type 1 diabetes (T1D) is associated with elevated CVD despite normal lipids, while in liver failure low plasma lipids may indicate increasing hepatic damage. Plasma lipids can therefore belie underlying dysregulated lipid metabolism. Islet (ITx) or liver (LTx) transplants represent therapies for T1D and liver failure, respectively, but are associated with altered lipid metabolism attributed to immunosuppressive medications; however, causative mechanisms are unknown. Partial success of dietary therapy in post-transplant patients may be due to interventions limited in scope. Regulation of plasma lipids involve absorption, synthesis, and clearance. These studies examined lipogenesis and cholesterol synthesis using deuterium incorporation. In brittle T1D lipogenesis and cholesterol synthesis were similar to healthy controls; however hepatic lipogenesis and cholesterol synthesis tended to be lower in T1D compared to matched control subjects. Plasma cholesterol was lower and triglyceride similar in liver failure patients compared to controls. Lipogenesis was higher while cholesterol synthesis was lower in liver failure compared to controls. Disturbances in lipid synthesis may be influenced by underlying disease, such as hepatitis C. In ITx and LTx lipogenesis was lower whereas cholesterol synthesis was similar compared to controls. Lipid synthesis is therefore unlikely to contribute to post-transplant hyperlipidemia, inviting investigation of other mechanisms. Dietary intervention emphasizing fish oil, phytosterols, soy, fibers, and almonds lowered plasma lipids in controls but had mixed effects in transplant subjects. Reduction in plasma lipids occurred in transplant patients with higher baseline lipids, suggesting this intervention may be successful in hyperlipidemic patients; however the potential of this diet intervention requires further study in hyperlipidemic patients. Diet intervention lowered lipogenesis but did not significantly change 24h cholesterol synthesis in controls. Diet did not change 24h lipogenesis or cholesterol synthesis in transplant subjects. Plasma lipid response to dietary therapy was related to baseline cholesterol synthesis and to dietary compliance in transplant subjects. Further study is required to determine if cholesterol synthesis is predictive of response to diet. / Nutrition and Metabolism