Type 1 diabetes is one of the most common chronic conditions in childhood and adolescence. Despite ongoing development of more physiological insulin preparations, recent advancements in insulin pump technology and more accurate blood glucose monitoring, in clinical practice it remains challenging to achieve normoglycaemia whilst reducing the risk of hypoglycaemia, particularly in young people with type 1 diabetes. Closed-loop insulin delivery (the artificial pancreas) is an emerging technology gradually progressing from bench to clinical practice. Closed-loop systems combine glucose sensing with computer-based algorithm informed insulin delivery to provide real-time glucose-responsive insulin administration. The key objective of my thesis is to evaluate the safety, efficacy and utility of closed-loop insulin delivery in children and adolescents with type 1 diabetes outside of the research facility setting. Results of five clinical trials are presented in the main chapters of this thesis. In a mechanistic study, the impact of glucose sensor operation duration on efficacy of overnight closed-loop was investigated comparing closed-loop performance on day 1 of sensor insertion to day 3 to 4 of sensor. Twelve adolescents with type 1 diabetes attended the research facility for two overnight visits. The sequence of the interventions was random. Despite differences in sensor accuracy, overnight CL glucose control informed by sensor glucose on day 1 or day 3-4 after sensor insertion was comparable. The model predictive controller appears to mitigate against sensor inaccuracies. In home settings, overnight closed-loop application was evaluated over three months in 25 children and adolescents with type 1 diabetes aged six to 18 years. The study was conducted at three centres in the UK and adopted a randomised cross-over design. Compared to sensor-augmented pump therapy, overnight home use of closed-loop increased the proportion of time sensor glucose was in target, and reduced mean glucose and hypoglycaemia. Two randomised crossover studies evaluated the safety and efficacy of day-and-night hybrid closed-loop insulin delivery in young people with type 1 diabetes aged 10 to 18 years over seven days, and 21 days, respectively. A total of 24 subjects were enrolled in this single centre trial. Free-living home use of day-and-night closed-loop in suboptimally controlled adolescents with type 1 diabetes was safe, and improved glucose control without increasing the risk of hypoglycaemia. Finally, closed-loop technology was assessed in five very young children (aged one to seven years) with type 1 diabetes in a two-period, crossover study. Closed-loop was used during both 3-week intervention periods, either with standard strength insulin (U100), or with diluted insulin (U20). The order of intervention was random. Free-living home use of day-and-night hybrid closed-loop in very young children with type 1 diabetes was feasible and safe. Glucose control was comparable during both intervention periods. Thus, use of diluted insulin during closed-loop insulin delivery might not be of additional benefit in this population. In conclusion, studies conducted as part of my thesis demonstrate that use of hybrid closed-loop insulin delivery systems in children and adolescents aged one to 18 years in free daily living without remote monitoring or supervision is feasible, safe and effective. My work supports the progression of this technology from research to mainstream clinical practice.

O diabetes mellitus tipo 1 é uma doença crônica que afeta principalmente a população infantojuvenil, e a sua incidência tem aumentado em todo o mundo. Diversos são os desafios enfrentados por essas crianças para o alcance do adequado manejo da doença. A não adesão ao tratamento e a escassez de intervenções estruturadas para essa clientela configuram a necessidade do desenvolvimento de novas estratégias educativas que sejam criativas, interativas e pautadas na valorização das suas necessidades e preferências. Nesse âmbito, os videogames têm surgido como estratégias educativas capazes de incorporar essas necessidades e promover a mudança positiva de comportamentos inadequados. Embora a literatura aponte o potencial uso dos videogames no suporte do manejo de doenças crônicas, registra-se a preocupação crescente sobre qual a melhor forma de desenvolver essas estratégias. A integração de princípios teóricos e metodológicos é recomendada, porém pouco descrita e explorada nos estudos. Este estudo objetiva desenvolver uma estrutura conceitual para fundamentar o desenvolvimento de videogames para crianças com diabetes mellitus tipo 1. Trata-se de um estudo metodológico que descreve os passos para o desenvolvimento dessa estrutura conceitual, considerando as Teorias de Mudança de Comportamentos em Saúde e a abordagem centrada no usuário como referenciais teóricos e metodológicos, respectivamente. Realizou-se estudo descritivo e transversal, de natureza quantitativa, para o levantamento do perfil das crianças e adolescentes com diabetes mellitus tipo 1, usuários de um hospital público do interior paulista, para conhecer com mais propriedade os futuros usuários do videogame. Em seguida, foram realizados dois ciclos de grupos focais, totalizando 11 grupos, com a participação de 21 crianças entre 7 e 12 anos. Realizou-se análise de conteúdo dedutiva e indutiva desses dados e elaborou-se a categoria central \"Um jogo feito pra mim\". Identificamos preferências quanto aos jogos de videogames e também as necessidades de aprendizagem relacionadas ao conhecimento sobre a doença e aquelas relativas às tarefas de autocuidado e, com isso, comportamentos inadequados dessas crianças. As crianças elencaram suas preferências quanto ao desenho de um videogame voltado para elas, com foco nos resultados identificados previamente. A seguir, relacionamos os resultados obtidos com os determinantes de mudanças de comportamentos em saúde e descrevemos, para cada um, suas influências no comportamento das crianças. Finalmente, a estrutura conceitual foi desenvolvida, mediante os passos cumpridos anteriormente, com base nas Teorias de Mudança de Comportamentos em Saúde e seus determinantes. A estrutura conceitual propõe um videogame que contempla seis fases, cada qual abordando um estágio de mudança de comportamento e determinantes específicos, alinhados às necessidades e preferências identificadas junto às crianças participantes. Apresentamos a aplicabilidade dessa estrutura, considerando cada fase proposta. Os resultados deste estudo contribuem para o avanço nas discussões de como as teorias de mudança de comportamento e seus determinantes devem estar relacionados ao desenho de tecnologias interativas. Ainda, este estudo auxilia pesquisas futuras cujos objetos de estudo sejam o desenvolvimento de videogames, para crianças com diabetes, que sejam agentes de mudanças e ao mesmo tempo criativos e divertidos / Type 1 diabetes mellitus is a chronic illness that mainly affects the child-juvenile population, and its incidence has increased all over the world. These children face different challenges to achieve the appropriate management of the disease. Non-compliance with the treatment and the lack of structured interventions for these clients entail the need to develop new educational strategies that are creative, interactive and based on the valuation of their needs and preferences. In that context, videogames have emerged as educational strategies capable of incorporating these needs and promoting positive change in inappropriate behaviors. Although the literature appoints the potential use of videogames to support the management of chronic illnesses, there is growing concern with the best way to develop these strategies. The integration of theoretical and methodological principles is recommended, but hardly described and explored in research. This study aims to develop a conceptual framework to support the development of videogames for children with type 1 diabetes mellitus. A methodological study was undertaken that describes the steps for the development of this conceptual framework, in view of the Health Behavior Change Theories and the User- Centered Design approach as theoretical and methodological frameworks, respectively. A descriptive and cross-sectional quantitative study was developed to survey the profile of children and adolescents with type 1 diabetes mellitus, who attend a public hospital in the interior of the State of São Paulo, so as to get to know the future videogame users more properly. Next, two cycles of focus groups were held, totaling 11 groups, in which 21 children between 7 and 12 years participated. These data were subject to deductive and inductive content analysis and a central category was elaborated named \"A game made for me\". We identified preferences regarding the use of videogames, as well as the learning needs related to the knowledge on the disease and to the self-care tasks and, thus, these children\'s inappropriate behaviors. The children listed their preferences for the design of a videogame aimed at them, focused on the previously identified results. Next, we relate the results obtained with the determinants of health behavior changes theories and we describe, for each of them, their influences on the children\'s behavior. Finally, the conceptual framework was developed through the steps developed earlier, based on the Health Behavior Changes Theories and their determinants. The conceptual framework proposed a videogame that consists of six phases, each of which addresses one stage of behavior change and specific determinants, aligned with the needs and preferences identified among the participating children. We present the applicability of this framework in view of each phase proposed. The results of this study contribute to advance in the discussions on how the behavioral theories and their determinants should be related to the design of interactive technologies. In addition, this study supports future studies aimed at developing videogames for children with diabetes, to serve as agents of change and, at the same time, be creative and funny

Diabetes is a growing chronic disease and a worldwide problem. Without any available cure in sight for the public other methods needs to be applied to increase the life quality of diabetic patients. Artificial Pancreas (AP), a concept of having a closed loop system to control the glucose level on Type 1 Diabetes (T1D) patients has been introduced and is under development. In this thesis, Model Predictive Control (MPC) has been re implemented from scratch in MATLAB/SIMULINK with associated Kalman filter and prediction function. It was implemented in the latest version of the UVA/Padova Simulator which is a tool approved by FDA for simulating diabetes treatment in order to speed up the AP development. Different MPC cost functions where tested together with integral action on a simplified system using a linear approximation of a population model. It was implemented and tuned with a new simulation tuning method using Genetic Algorithm (GA). It showed that the quadratic cost function without integral action was the best with respect to performance and time efficiency. 3 hours was the best prediction horizon and was used for the individualized tuning using the University of Virginia (UVA)/Padova simulator. For the individualized MPC, models identified by the University of Padova were used. These simulations showed that an individualized model could be used for improved T1D treatment compared to an average population model even though the results were mixed. Almost all of the patients got improved treatment with the closed treatment and non hypoglycemic event occurred. The identification of better models is a great challenge for the future development of the AP MPC due to the excitation problems.

Introduction: In Sweden, 450,000 people suffer from diabetes, of which 10-15% have type 1 diabetes. Individuals who have lived with the disease for a long time run the risk of complications. Physical activity is central to the treatment, but there are risks and obstacles that can lead to the individual avoiding physical activity.  Aim: The purpose is to investigate perceived risks and other obstacles during physical activity for type 1 diabetics.  Methods: The choice of method was a systematic literature study. The databases WorldCat Discovery and Pubmed were used in the search of reports. After the search, 10 reports were selected, and a thematic analysis was applied. Then 3 themes were chosen which were later used to analyze the reports. They were as follows: the fear and the risk of hypoglycemia, the obstacles and remedies in relation to physical activity and behavioral changes in the individual.  Results: The fear of a hypoglycemia prevents the individual from exercising. The result showed that women suffers from anxiety concerning their diabetes to a greater extent than men. Aids such as Continuous Glucose Monitoring can minimize anxiety and the risk of getting into hypoglycemia during physical activity.  Conclusion: Constantly worrying about getting into hypoglycemia can cause the individual to stop caring for the risks associated with the disease. One of the factors that led to the individual being unable to perform physical activity was hyperglycaemia. Continuous blood glucose monitoring as well as support of personnel at exercise facilities can lead to the individual overcoming obstacles and concerns.

Diabetes can affect the structure and function of the foot, resulting in severe limitation of mobility and reduction of life expectancy. Early warning signs include limited joint mobility (LJM), soft tissue changes, high plantar pressure (HPP), high pressure time integrals (P/TI) and plantar callus. These abnormalities were examined in 216 young people with diabetes and 57 controls. The fingers, toes, ankle subtalar and first metatarsophalangeal joints shows reduced motion and the plantar aponeurosis was thicker in diabetic subjects. Skin thickness was the same for diabetic and control subjects. LJM in the feet was more common in males and older subjects. Subtalar and finger LJM was associated with early sensory nerve changes and finger LJM was associated with retinopathy and higher HbAtc. Thicker plantar aponeurosis was associated with male gander and larger feet. High peak pressure, high P/TI and callus were no more common in diabetic subjects than controls. However, high P/TI and callus were associated with early sensory nerve changes in young people with diabetes. Diabetic subjects with callus were significantly older than those without callus. Those with HPP had higher body mass index and less motion at the first MTP joints than those without HPP. Although plantar callus, HPP and high P/TI were no more common in young people with diabetes these abnormailities may be complicated by diabetes. Cushioning, custom orthoses or both in combination significantly reduced peak pressure and P/TI in diabetic subjects. / Doctor of Philosophy (PhD)

<p>Type 1 diabetes is caused by immuno-mediated β-cell destruction leading to insulin deficiency and hyperglycaemia. The decline in β-cell function and the clinical course after diagnosis vary. Whether the process of destruction of the β-cells is associated with markers of a non-specific inflammatory response is unknown. The aims of these studies were to identify factors of importance for clinical remission (low insulin need and normoglycaemia) and long-term β-cell function and estimate the degree of non-inflammatory response in type 1 diabetes in young adults. Clinical remission and β-cell function eight years after diagnosis were assessed and related to clinical, biochemical and immunological variables at diagnosis, including islet autoantibodies [ICA, GADA, IA-2A]. Markers of low-grade inflammation in plasma [CRP and IL-6] were estimated and the concentrations were related β-cell function [plasma C-peptide], glycaemic control and autoimmunity at diagnosis and the first year thereafter. The results showed that clinical remission occurred in about half of the patients with newly diagnosed type 1 diabetes. Preserved β-cell function eight years after diagnosis was observed in 16% of the patients classified at diagnosis as having autoimmune type 1 diabetes. Duration of remission was dependent on BMI, degree of metabolic derangement and presence of GADA at diagnosis. BMI at diagnosis was also of importance for preserved β-cell function after eight years of the disease, as were the amount of islet antibodies and presence of ICA. Elevated CRP levels were noted in the majority of cases at diagnosis and both CRP and IL-6 concentrations were stable the first year after clinical diagnosis. High concentrations of CRP and IL-6 did not relate to β-cell destruction or the degree of autoimmunity. CRP concentrations were higher in islet antibody negative than in positive patients. CRP also correlated positively to BMI, C-peptide at 12 months and to increasing HbA1c between six and 12 months. In general, females had shorter remissions, lower concentrations of serum bicarbonate and higher levels and prevalence of GADA at diagnosis, compared to males. Females also had higher HbA1c and CRP values the first year after diagnosis. In summary, BMI at diagnosis is a strong predictor of duration of remission and preservation of β-cell function. Elevated CRP concentrations are correlated to factors linked rather to insulin resistance than to β-cell destruction. Females appear to have a more acute onset and a more severe course of the disease than males.</p>

<p>Excessive weight gain has frequently been reported in adolescents with type 1 diabetes, especially in girls. In general, puberty is associated with reduced insulin sensitivity that is further diminished by overweight. The causes and consequences of excessive weight gain in adolescents with type 1 diabetes are not fully understood. The studies described in this thesis addressed body composition in adolescents with type 1 diabetes and the relationships between physical activity, energy intake and changes in body composition. Furthermore, the effect of metformin as additional therapy on glycaemic control and insulin sensitivity was examined in a randomised placebo-controlled study. Body mass index (BMI) and percentage body fat (%BF) were significantly higher in girls with type 1 diabetes compared to healthy control girls. Mean HbA1c during puberty, but not mean insulin dose, was positively related to BMI at the age of 18 in girls with diabetes. A centralised fat distribution was associated with poor glycaemic control, increased daily dosage of insulin and elevated cholesterol and triglyceride levels. Neither total physical activity nor total energy intake differed between adolescent girls with type 1 diabetes and healthy age-matched control girls. A high dietary fat intake was positively related to gain in %BF in girls with type 1 diabetes. Additional therapy with metformin for three months improved glycaemic control and peripheral insulin sensitivity in adolescents with poorly controlled type 1 diabetes. The improvement in glycaemic control was related to insulin sensitivity at baseline, implying that the most insulin resistant subjects benefited most from the metformin therapy. It is concluded that the excessive weight gain observed in girls with type 1 diabetes is mainly attributable to an increased fat mass and that dietary fat intake is of importance for this gain in body fat. Additional treatment with metformin improves glycaemic control in adolescents with poorly controlled type 1 diabetes.</p>

<p>The process of β-cell destruction that leads to type 1 diabetes (T1D) is incompletely understood and it is believed to be a result of both genetic and environmental factors. Enterovirus (EV) infections of the β-cells have been proposed to be involved, however, the effects of EV infections on human β-cells have been little investigated. This thesis summarises studies of three different Coxsackie B4 virus strains that have previously been shown to infect human islets. The effects of infections with these EV were studied <i>in vitro</i> in human islets and in a rat insulin-producing cell line. In addition, a pilot study was performed on isolated human islets to investigate the ability to treat such infections with an antiviral compound.</p><p>It was found that one of the virus strains replicated in human β-cells without affecting their main function for at least seven days, which <i>in vivo</i> may increase a virus’s ability to persist in islets.</p><p>Nitric oxide was induced by synthetic dsRNA, poly(IC), but not by viral dsRNA in rat insulinoma cells in the presence of IFN-γ, suggesting that this mediator is not induced by EV infection in β-cells and that poly(IC) does not mimic an EV infection in this respect.</p><p>All three virus strains were able to induce production of the T-cell chemoattractant interferon-γ-inducible protein 10 (IP-10) during infection of human islets, suggesting that an EV infection of the islets might trigger insulitis <i>in vivo</i>.</p><p>Antiviral treatment was feasible in human islets, but one strain was resistant to the antiviral compound used in this study.</p><p>To conclude, a potential mechanism is suggested for the involvement of EV infections in T1D. If EV infections induce IP-10 production in human islet cells <i>in vivo</i>, they might recruit immune cells to the islets. Together with viral persistence and/or virus-induced β-cell damage, this might trigger further immune-mediated β-cell destruction <i>in vivo</i>.</p>

Type 1 diabetes is caused by immuno-mediated β-cell destruction leading to insulin deficiency and hyperglycaemia. The decline in β-cell function and the clinical course after diagnosis vary. Whether the process of destruction of the β-cells is associated with markers of a non-specific inflammatory response is unknown. The aims of these studies were to identify factors of importance for clinical remission (low insulin need and normoglycaemia) and long-term β-cell function and estimate the degree of non-inflammatory response in type 1 diabetes in young adults. Clinical remission and β-cell function eight years after diagnosis were assessed and related to clinical, biochemical and immunological variables at diagnosis, including islet autoantibodies [ICA, GADA, IA-2A]. Markers of low-grade inflammation in plasma [CRP and IL-6] were estimated and the concentrations were related β-cell function [plasma C-peptide], glycaemic control and autoimmunity at diagnosis and the first year thereafter. The results showed that clinical remission occurred in about half of the patients with newly diagnosed type 1 diabetes. Preserved β-cell function eight years after diagnosis was observed in 16% of the patients classified at diagnosis as having autoimmune type 1 diabetes. Duration of remission was dependent on BMI, degree of metabolic derangement and presence of GADA at diagnosis. BMI at diagnosis was also of importance for preserved β-cell function after eight years of the disease, as were the amount of islet antibodies and presence of ICA. Elevated CRP levels were noted in the majority of cases at diagnosis and both CRP and IL-6 concentrations were stable the first year after clinical diagnosis. High concentrations of CRP and IL-6 did not relate to β-cell destruction or the degree of autoimmunity. CRP concentrations were higher in islet antibody negative than in positive patients. CRP also correlated positively to BMI, C-peptide at 12 months and to increasing HbA1c between six and 12 months. In general, females had shorter remissions, lower concentrations of serum bicarbonate and higher levels and prevalence of GADA at diagnosis, compared to males. Females also had higher HbA1c and CRP values the first year after diagnosis. In summary, BMI at diagnosis is a strong predictor of duration of remission and preservation of β-cell function. Elevated CRP concentrations are correlated to factors linked rather to insulin resistance than to β-cell destruction. Females appear to have a more acute onset and a more severe course of the disease than males.

Excessive weight gain has frequently been reported in adolescents with type 1 diabetes, especially in girls. In general, puberty is associated with reduced insulin sensitivity that is further diminished by overweight. The causes and consequences of excessive weight gain in adolescents with type 1 diabetes are not fully understood. The studies described in this thesis addressed body composition in adolescents with type 1 diabetes and the relationships between physical activity, energy intake and changes in body composition. Furthermore, the effect of metformin as additional therapy on glycaemic control and insulin sensitivity was examined in a randomised placebo-controlled study. Body mass index (BMI) and percentage body fat (%BF) were significantly higher in girls with type 1 diabetes compared to healthy control girls. Mean HbA1c during puberty, but not mean insulin dose, was positively related to BMI at the age of 18 in girls with diabetes. A centralised fat distribution was associated with poor glycaemic control, increased daily dosage of insulin and elevated cholesterol and triglyceride levels. Neither total physical activity nor total energy intake differed between adolescent girls with type 1 diabetes and healthy age-matched control girls. A high dietary fat intake was positively related to gain in %BF in girls with type 1 diabetes. Additional therapy with metformin for three months improved glycaemic control and peripheral insulin sensitivity in adolescents with poorly controlled type 1 diabetes. The improvement in glycaemic control was related to insulin sensitivity at baseline, implying that the most insulin resistant subjects benefited most from the metformin therapy. It is concluded that the excessive weight gain observed in girls with type 1 diabetes is mainly attributable to an increased fat mass and that dietary fat intake is of importance for this gain in body fat. Additional treatment with metformin improves glycaemic control in adolescents with poorly controlled type 1 diabetes.