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Tonåringars och ungdomars upplevelser av att leva med typ 1- diabetesEvelina, Malmin January 2016 (has links)
Bakgrund: Typ- 1 diabetes är en autoimmun sjukdom som behandlas med tillförsel av insulin, goda matvanor och regelbunden fysisk aktivitet. Sjukdomen drabbar ofta barn och ungdomar som beskriver en svårighet att balansera egenvården med vardagslivet. Syfte: Att belysa tonåringars och ungdomars upplevelser av att leva med typ 1- diabetes. Metod: En litteraturstudie genomfördes, 8 kvalitativa artiklar inkluderades i resultatet och analyserades genom Fribergs metod. Resultat: Fem kategorier skapades vid analys: Relationer till omgivningen, stöd respektive brist på stöd från omgivningen, förlorad autonomi, känslomässiga och fysiska reaktioner och hantering och anpassning. Konklusion: Att leva med typ-1 diabetes kan vara tufft på många sätt för tonåringar och ungdomar. De beskriver svårigheter i samband med att vara beroende av föräldrar och vuxna samt en osäkerhet i hanteringen av sjukdomen vilket kan förvärra situationen. Att tidigt involvera tonåringarna och ungdomarna i deras egenvård kan hjälpa dem att känna sig mer självsäkra och bli självständiga i hanteringen av sjukdomen. / Background: Type 1 diabetes is an autoimmune disease which is treated with insulin, good eating habits and physical activity. The disease is more common in children and young people who describe difficulties to balance their self-care with their everyday life. Aim: To elucidate teenagers and young people's experiences of living with type 1 diabetes. Method: A literature study was performed. Eight qualitative articles was included in the results and was analyzed according to Friberg’s method for literature review. Results: Five categories were created during the analysis: The relationships to the surrounding, support and lack of support from the surroundings, lost autonomy, emotional and physical reactions and management and adjustment. Conclusions: Living with type 1 diabetes can be tough for teenagers and young people in many ways. They describe difficulties associated with being dependent of parents and adults as well as insecurity in the management of the disease which might worsen the situation. To involve teenagers and young people in self-care activities at an earlier age might help them to feel more confident and become more independent in the management of the disease.
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Identification and characterization of the endoplasmic reticulum (ER)-stress pathways in pancreatic beta-cells/Identification et caractérisation des voies de signalisation du stress du réticulum endoplasmique dans la cellule bêta pancréatiquePirot, Pierre 26 November 2007 (has links)
The endoplasmic reticulum (ER) is the organelle responsible for synthesis and folding of secreted and membranous protein and lipid biosynthesis. It also functions as one of the main cellular calcium stores. Pancreatic beta-cells evolved to produce and secrete insulin upon demand in order to regulate blood glucose homeostasis. In response to increases in serum glucose, insulin synthesis represents nearly 50% of the total protein biosynthesis by beta-cells. This poses an enormous burden on the ER, rendering beta-cells vulnerable to agents that perturb ER function. Alterations of ER homeostasis lead to accumulation of misfolded proteins and activation of an adaptive response named the unfolded protein response (UPR). The UPR is transduced via 3 ER transmembrane proteins, namely PERK, IRE-1 and ATF6. The signaling cascades activated downstream of these proteins: a) induce expression of ER resident chaperones and protein foldases. Increasing the protein folding capacity of the ER; b) attenuate general protein translations which avoids overloading the stressed ER with new proteins; c) upregulate ER-associated degradation (ERAD) genes, which decreases the unfolded protein load of the ER. In severe cases, failure by the UPR to solve the ER stress leads to apoptosis. The mechanisms linking ER stress to apoptosis are still poorly understood, but potential mediators include the transcription factors Chop and ATF3, pro-apoptotic members of the Bcl-2 familly, the caspase 12 and the kinase JNK.
Accumulating evidence suggest that ER stress contributes to beta-cell apoptosis in both type 1 and type 2 diabetes. Type 1 diabetes is characterized by a severe insulin deficiency resulting from chronic and progressive destruction of pancreatic beta-cells by the immune system. During this autoimmune assault, beta-cells are exposed to cytokines secreted by the immune cells infiltrating the pancreatic islets. Our group has previously shown that the pro-inflamatory cytokines interleukin-1beta (IL1-beta and interferon-gamma (IFN-gamma), via nitric oxide (NO) formation, downregulate expression and function of the ER Ca2+ pump SERCA2. This depletes beta-cell ER Ca2+ stores, leading to ER stress and apoptosis. Of note, IL1-beta alone triggers ER stress but does not induce beta-cell death, while IFN-gamma neither causes ER stress nor induces beta-cell death. Together, these cytokines cause beta-cell apoptosis but the mechanisms behind this synergistic effect were unknown.
Type 2 diabetes is characterized by both peripheral resistance to insulin, usually as a result of obesity, and deficient insulin secretion secondary to beta cell failure. Obese patients have high levels of circulating free fatty acids (FFA) and several studies have shown that the FFA palmitate induces ER stress and beta-cell apoptosis.
In the present work we initially established an experimental model to specifically activate the ER stress response in pancreatic beta-cells. For this purpose, insulinoma cells (INS-1E) or primary rat beta-cells were exposed to the reversible chemical SERCA pump blocker cyclopiazonic acid (CPA). Dose-response and time course experiments determined the best conditions to induce a marked ER stress without excessive cell death (<25%).
The first goal of the work was to understand the synergistic effects of IL1-beta and IFN-gamma leading to pancreatic beta-cell apoptosis. Our group previously observed, by microarray analysis of primary beta-cells, that IFN-gamma down-regulates mRNAs encoding for some ER chaperones. Against this background, our hypothesis was that IFN-gamma aggravates beta-cell ER stress by decreasing the ability of these cells to mount an adequate UPR. To test this hypothesis, we investigated whether IFN-gamma pre-treatment augments CPA-induced ER stress and beta cell death. The results obtained indicated that IFN-gamma pre-treatment potentiates CPA-induced apoptosis in INS-1E and primary beta-cells. This effect was specific for IFN-gamma since neither IL1-beta nor a low dose CPA pre-treatment potentiated CPA-induced apoptosis in INS-1E cells. These effects of IFN-gamma were mediated via the down regulation of genes involved in beta cell defense against ER stress, including the ER chaperones BiP, Orp150 and Grp94 as well as Sec61, a component of the ERAD pathway. This had functional consequences as evidenced by a decreased basal and CPA-induced activity of a reporter construct for the unfolded protein response element (UPRE) and augmented expression of the pro-apoptotic transcription factor Chop.
We next investigated the molecular regulation of the Chop gene in INS-1E cells in response to several pro-apoptotic and ER stress inducing agents, namely cytokines (IL1-beta and IFN-gamma), palmitate, or CPA. Detailed mutagenesis studies of the Chop promoter showed differential regulation of Chop transcription by these compounds. While cytokines (via NO production)- and palmitate-induced Chop expression was mediated via a C/EBP-ATF composite and AP-1 binding sites, CPA induction required the C/EBP-ATF site and the ER stress response element (ERSE). Cytokines, palmitate and CPA induced ATF4 protein expression and further binding to the C/EBP-ATF composite site, as shown by Western blot and EMSA experiments. There was also formation of distinct AP-1 dimers and binding to the AP-1 site after exposure to cytokines or palmitate.
The third objective of this work was to obtain a broad picture of the pancreatic beta-cell molecular responses during and after (recovery period) a severe ER stress. For this purpose, we utilized an “in home” spotted microarray, the APOCHIP, containing nearly 600 probes selected for the study of beta-cell apoptosis. Time-dependent gene expression profiles were measured in INS-1E cells exposed to CPA. CPA-induced ER-stress modified expression of 183 genes in at least one of the time points studied. Most of theses genes returned to control levels 3h after CPA removal from the culture medium. We observed full beta-cell recovery and survival, indicating that these cells trigger efficient defenses against ER stress. Beta-cell recovery is associated with a sustained increase in the expression of ER chaperones and a rapid decrease of pro-apoptotic mRNAs following CPA removal. Two groups of genes were particularly affected by CPA, namely those related to the cellular responses to ER stress, which were mostly up-regulated, and those related to differentiated beta-cell functions, which were down-regulated. Among this last group, we observed a 40-90% decrease of the mRNAs for insulin-1 and -2. These findings were confirmed in INS-1E cells exposed to cytokines or thapsigargin (another SERCA blocker), and in primary beta-cells exposed to the same treatments. This decrease in insulin mRNA expression is due to transcript degradation, most probably caused by IRE-1 activation and triggering of its endoribonuclease activity, as recently described in Drosophila cells.
In conclusion, our work enabled a better understanding of the pancreatic beta-cell responses to ER stress:
1.)We identified a sensitizing effect of IFN-gamma to ER stress in beta-cells via downregulation of key ER chaperones.
2.)We observed a differential regulation of Chop transcription by different treatments suggesting distinct responses of pancreatic beta-cells to diverse ER stress inducers.
3.)We provided the first global analysis of gene expression modifications in pancreatic beta-cells following ER stress.
4.)We demonstrated a high capacity of beta-cells to cope and recover from a severe ER stress.
5.)We identified a new protective mechanism against ER stress, namely the degradation of insulin mRNA which limits the load posed on the ER by insulin synthesis. This, coupled to a marked increase in ER chaperones and a fast degradation of pro-apoptotic mRNAs, enables beta cells to recover from ER stress after the causes of this stress are removed.
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Population mixing and the geographical epidemiology of childhood leukaemia and type 1 diabetes in New ZealandMiller, Laura Jean January 2008 (has links)
Over the past twenty years the incidence of both childhood acute lymphoblastic leukaemia (ALL) and type 1 diabetes have risen in many developed countries, including New Zealand. Although the explanations for this increase and the precise aetiology of both diseases remain unclear, environmental factors are thought to be important. One factor receiving increasing attention is the role of infections introduced through population mixing. However, previous studies on this topic show mixed results and population mixing itself tends to be under-theorised. Furthermore, this issue has not been adequately assessed in New Zealand, a country characterised by high levels of population mobility. In this research, a variety of population mixing measures for small areas in New Zealand were developed. National data on ALL registrations were obtained from the New Zealand Cancer Registry, and regional type 1 diabetes data were obtained from the Canterbury Diabetes Register for the Canterbury Region of the South Island. The analyses were undertaken in three stages. First, standardised incidence ratios of each disease were examined at different geographical and temporal scales, between areas of differing socioeconomic status, and in urban and rural New Zealand. Second, cluster analysis was employed to test for spatial-temporal clustering of the two diseases. Finally, multivariate regression analyses were utilised to investigate the association between each disease and the various measures of population mixing at the area-level. The results reveal similarities in the geographical epidemiology of childhood ALL and type 1 diabetes in New Zealand. The majority of the findings were suggestive of an infectious aetiology for both diseases. In addition, higher incidence of both diseases was observed in areas which increased the most in population mixing over short time periods (6/7 years). Furthermore, raised type 1 diabetes incidence was also associated with high population mixing in early life.
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Adolescents' experience of 'adjustment' to life with diabetes : an interpretative phenomenological analysisFoster, Emily January 2010 (has links)
Aim: A wealth of quantitative literature exists exploring the adjustment of children and young people with Type 1 Diabetes Mellitus. However, results are often confusing and contradictory, at least partly due to studies using different definitions and measures. Studies have been criticised for over relying on parental reports and failing to consider young people’s own perceptions. Furthermore, they have often conceptualised adjustment as an outcome, rather than exploring the process involved. Additionally, although peers are considered to play an important role in young people’s lives, their role in young people’s adjustment to living with diabetes has rarely been examined. To address this gap, this study attempted to gain a rich understanding of young people’s experiences of adjusting to life with diabetes and explore how they feel their peers have contributed to this process, with the hope of informing clinical practice and improving support to young people and their families. Method: A qualitative approach was chosen and six young females aged 12 – 15 with a diagnosis of Type 1 diabetes were interviewed using semi-structured interviews. Interpretative Phenomenological Analysis was used to analyse the transcripts. Results: Five main themes emerged from participants’ accounts: Developing a balanced relationship with diabetes; the uncomfortable position of difference; grappling with the fall out of diabetes; making diabetes more bearable; and the role of parents and friends. The findings are discussed in relation to the relevant literature. Clinical implications, methodological limitations and directions for future research are presented. Conclusions: This study provided an insight into the complex and dynamic process of young people’s adjustment to life with Type 1 diabetes. It highlighted the challenges and struggles they faced as a result of their diagnosis and the different strategies they employed to manage these. It also emphasised the valuable role both parents and friends provide in supporting young people with their illness.
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The effects of aerobic and resistance exercise on inflammatory markers and metabolic control in healthy individuals and type 1 diabetics using either insulin pump or multiple dose injectionAlblihed, Mohamd Abdulrahman January 2013 (has links)
Type 1 diabetes (T1D) is characterised by an absolute insulin deficiency resulting from the chronic and progressive destruction of pancreatic β-cells by the immune system cells. Continuous subcutaneous insulin infusion (CSII) is becoming a popular technique for insulin delivery among T1D patients. Exercise is known to exert anti-inflammatory effects and metabolic control. Therefore it was of interest to study this in T1D using CSII. The objectives of this thesis were to further understanding of the effect of exercise on blood glucose, hemoglobin A1c, lipids, insulin and inflammatory markers in healthy and T1D volunteers. Three studies have been investigated where the diabetic volunteers used multi daily injections (MDI) or CSII. Firstly a survey was conducted aimed to investigate the effect of exercise on T1D patients using CSII therapy. The second study examined the acute and chronic effects of resistance and cardio exercise at moderate intensity on inflammatory markers such as IL-6, IL-1β, TNF-α and IFN-γ in healthy and T1D using MDI or CSII. Finally, a study was undertaken to find out the effects of chronic moderate intensity exercise on lipids profile and glycaemic control in healthy and T1D using MDI or CSII. The statistical analysis of the survey showed that CSII therapy for T1D had a significant reduction on A1c, insulin requirement and improvement of lipids profile compared to MDI. Moreover, majority of CSII users (63%) rarely suffered from hypoglycemia during exercise. The second study demonstrated that acute and chronic exercises have a positive impact on the inflammatory markers among CSII users e.g. in CSII users statistically significant increase in IL-6 and TNF-α levels were observed (P=0.014 and P=0.001 respectively). The last study showed that lipids profile, total daily insulin units were improved and A1c levels were significantly reduced in CSII as well as MDI groups after 6 weeks of exercise. T1D affects major organs e.g. heart, kidneys, blood vessels etc. However, good glycaemic control can reduce the risk of diabetes complications. This study suggested that CSII therapy along with exercise can maintain the BG level close to normal, as all 5 participants of the study showed an improvement in their BG levels after exercise.
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Do attachment security, self-esteem and emotional distress predict metabolic control and quality of life in adolescents with Type 1 diabetes? : will 'wellbeing' text-messaging support improve outcomes?Swan, Mary January 2012 (has links)
Objectives: Systematic review: This article presents a systematic review of studies evaluating the evidence for mobile phone-based interventions with adolescents who have Type 1diabetes. Studies were critically appraised and findings synthesised with the aim of answering the question: do mobile phone technologies facilitate improved outcomes in adolescents who have Type 1diabetes? Empirical research study: Diabetes research has indicated an association between attachment security and metabolic control as well as increased prevalence of mental health difficulties in diabetes populations. There is limited research with an adolescent Type 1 diabetes population. The current study aimed to examine attachment, emotional distress and self-esteem in an adolescent Type 1 diabetes population in relation to metabolic control and quality of life. The current study also aimed to evaluate the impact of ‘wellbeing text-messaging support’ with the same population. Method: Systematic review: A systematic search strategy was employed to identify relevant studies. An electronic database search, combined with a hand search of key journals and reference sections of key papers, was undertaken. Methodological quality was determined using an idiosyncratic measure including information relating to study design, sample size, interventions and statistical analyses. A narrative synthesis was performed due to the heterogeneity of the sample. Empirical research study: 60 participants aged between 12-18 years old who had a diagnosis of Type 1 diabetes for over 12 months took part. A longitudinal questionnaire design was used to collect data using five validated psychological measures. HbA1c was used as a measure of metabolic control. Text-messaging comprised a wellbeing module delivered daily over a three-week period. Results: Systematic review: 12 eligible studies were identified. One achieved a rating of ‘very good’, two a rating of ‘good’ and the remaining nine were pilot and/or feasibility studies, of whom four received a rating of ‘fair’ and ‘five received a rating of ‘poor’ methodological quality. Results indicated limited good quality evidence which included improved adherence and self-efficacy and mixed results in relation to metabolic control. Limitations identified included the use of small, convenience samples and short study duration. Empirical research study: High levels of fearful attachment security predicted poorer metabolic control and poorer quality of life, and high levels of emotional distress predicted poorer quality of life. ‘Wellbeing text-messaging support’ resulted in significantly improved quality of life. Conclusion: Systematic review: There is limited evidence that mobile phone technology has consistently improved outcomes in adolescents with Type 1 diabetes. Due to the number of pilot or feasibility studies and predominantly poor/fair quality of the current literature, and the heterogeneity of the sample, only tentative conclusions can be drawn, thus highlighting the need for further research. Empirical research study: Adolescent attachment style and emotional distress may be assessed as part of routine diabetes care in order to identify individuals who are potentially most at risk of failing to engage with diabetes health care. This can subsequently impact negatively on metabolic control and/or quality of life. These findings highlight the importance of clinical psychology input in paediatric diabetes teams. Further research in relation to text-messaging support was recommended.
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The importance of psychological and physical stressors on diabetes-related immunity in a young population – an interdisciplinary approachCarlsson, Emma January 2016 (has links)
Background: The prevalence of immunological disorders such as type 1 diabetes (T1D) is increasingly common amongst children, adolescents and young adults. There is also an increase in psychosomatic symptoms (depression, insomnia, anxiety, headaches and fatigue etc.) as well as a decrease in physical activity amongst young people, affecting the well-being and overall health of our younger population. It is therefore important to study the effects of psychological and physical stressors on the immune system, to evaluate their impact on juvenile health. Aim: This thesis explores the impact of psychological and physical stressors on the cellular immune system with special focus on diabetes-related immunity in a young population, using an interdisciplinary approach. Method: When exploring the impact of psychological and physical stressors such as psychological stress due to exposure to psychological stressful experiences or degree of physical activity/training on the cellular immune system in children, adolescents and young women, peripheral blood mononuclear cells (PBMC) were stimulated with antigens (tetanus toxoid (TT) and β-lactoglobulin (βLG)) as well as diabetes-related autoantigens (insulin, heat shock protein 60 (HSP60), tyrosine phosphatase-2 (IA-2) and glutamic acid decarboxylase 65 (GAD65)) and secreted cytokines and chemokines were measured by multiplex fluorochrome technique (Luminex). Populations of Thelper (Th) cells (CD4+), T-cytotoxic (Tc) cells (CD8+), B cells (CD19+), Natural Killer (NK) cells (CD56+CD16+) as well as regulatory T (Treg) cells (CD4+CD25+FoxP3+CD127-), and their expression of CD39 and CD45RA were studied by flow cytometry. Diabetes-related parameters (glucose, C-peptide,proinsulin, pancreatic polypeptide and peptide YY) were measured to studyβ-cell activity and appetite regulation and cortisol was used as a biological marker for psychological and physical stress. Results: Children in families exposed to psychological stress showed an imbalanced cellular immune response as well as an increased immune response towards diabetes-related autoantigens. Also, previous exposure to psychological stress as well as current exposure to psychological stress in young women showed an increased immune response towards diabetes-related autoantigens. Further, previous exposure to psychological stress in young women showed increased numbers of circulating CD56+CD16+ NK cells as wellas decreased numbers of circulating CD4+CD25+FoxP3+CD127- Treg cells. High physical activity in children showed decreased spontaneous immune response as well as a decreased immune response towards diabetes-related autoantigens, while low physical activity in children showed an increased immune response towards diabetes-related autoantigens. Further, endurance training in adolescents, especially in adolescent males and young adolescents, showed an increased immune response towards the diabetes-related autoantigen IA-2. Conclusion: It is evident that psychological and physical stressors such as exposure to psychological stress and degree of physical activity/training impact the cellular immune system. Experiences associated with psychological stress seem to have a negative effect on the cellular immune system in a young population, causing an imbalance in the immune system that could possibly induce diabetes-related immunity. High physical activity in children seems to have a protective effect against diabetes-related immunity. In contrast, low physical activity in children and endurance training in adolescents seems to induce diabetes-related immunity. It is very likely that psychological stressful experiences, low physical activity and intense training such as endurance training all play important roles in the immunological process leading to the development of type 1 diabetes.
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Att som ung vuxen leva med diabetes typ 1 : Individernas upplevelser / To live with type 1 diabetes as a young adult : the individuals experiencesLindqvist, Saga, Sundberg, Sara January 2017 (has links)
År 2012 avled 1.5 miljoner människor till följd av diabetes och förekomsten av sjukdomen ökar i världen hela tiden. Diabetes typ 1 betraktas som den allvarligaste formen av diabetes och varje år insjuknar 400 personer i åldrarna 15–34. Individen måste själv hantera 95% av sin egen diabetesvård vilket gör att hen ställs inför många krav att utföra olika former av livsstilsförändringar. Syftet med studien var att belysa unga vuxnas upplevelser av att leva med diabetes typ 1. Studien genomfördes som en systematiskt litteraturstudie med kvalitativ metod med en induktiv manifest design. Under databearbetningen framkom fem teman: upplevd rädsla, upplevelser av bristande kunskap, upplevelser av egenvård, upplevda svårigheter samt upplevelser av relationer och stöd. Resultatet i studien belyser svårigheter med egenvård, rädslor relaterade till sjukdomen, att känna sig annorlunda, svårigheter med att avslöja sin sjukdom, att känna sig dömd av andra på grund av deras okunskap, bristen på stöd och dåligt bemötande från vårdpersonal. Dessa upplevelser är viktig kunskap för sjuksköterskor för att ge en god omvårdnad och det kan vara intressant att genomföra vidare forskning kring hur individer upplever sjuksköterskans stöd samt vad sjuksköterskan kan göra för att främja egenvård. / In 2012, 1,5 million people died due to diabetes and the prevalence of the disease increases worldwide all the time. Type 1 diabetes is considered the most serious type of diabetes and every year 400 people in the ages 15-34 sicken in the disease. The individual must manage 95% of their diabetes management which puts him or her to be faced with a lot of demands to perform different kinds of lifestyle changes. The aim of this study was to illustrate young adults’ experiences of living with type 1 diabetes. The study was performed as a literature study with a qualitative methodology and inductive manifest design. In the data analysis five categories emerged: experienced fear, experiences of lack of knowledge, experiences of self-care management and experiences of relationships and support. The result of this study highlights the difficulties of self-care management, fears related to the disease, feeling different, the difficulties of disclosing the disease, feeling judged by others because of their lack of knowledge, lack of support and bad treatment from healthcare professionals. These experiences are important knowledge for nurses to give a good nurturance and it could be interesting to do further research about how individuals experience the support from the nurse and what the nurse can do to promote self-management.
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Immunopathology of the Pancreas in Type 1 DiabetesWiberg, Anna January 2016 (has links)
Type 1 diabetes (T1D) results from a loss of functional insulin-producing pancreatic beta cells. The etiology of T1D is poorly understood, but the detection of infiltrating inflammatory cells in the pancreas and circulating autoantibodies has led to the common notion that an autoimmune process plays a central role in the pathogenesis of the disease. The aim of this doctoral thesis was to assess various aspects of the immunopathology of type 1 diabetes. To this purpose, studies have been conducted on pancreatic material from the Network for Pancreatic Organ Donors with Diabetes (nPOD) collection, the Nordic Network for Islet Transplantation, and the Diabetes Virus Detection (DiViD) study. Paper I is a study on pancreatic tissue from organ donors with varying duration of T1D as well as non-diabetic donors and subjects with other types of diabetes, in which persistent expression of glucose transporters was shown on the beta cell membrane despite several years of T1D. Glucose transporter 1 was also confirmed as the predominant glucose transporter on human pancreatic islets. In paper II, we report on signs of inflammation in the exocrine but not in the endocrine pancreas in non-diabetic organ donors with diabetes-related autoantibodies, suggesting that diabetes-associated autoantibodies can occur in response to unspecific pancreatic lesions. Paper III aimed to characterize the T cell-infiltration of pancreatic islets in material from recent-onset T1D patients. Insulitis was shown in all subjects, but with distinct differences in expression analysis of T- and B cell activation to cell-mediated allorejected kidney transplant. Also Paper IV was conducted on material from recent-onset cases and showed increased islet glucagon content, in combination with a reduced number of islets but sustained mean islet size. Together, these results provide expansion of our knowledge of the immunopathology in T1D, and will hopefully assist in bringing us towards a deeper understanding of T1D aetiology and eventually an effective cure.
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The influence of donor body mass index on human pancreatic islet function, structure and islet transplant outcomeWalker, Jonathan Neil January 2011 (has links)
Background: Pancreatic islet transplantation for type-1 diabetes has resulted in considerable success over the past decade. However, the worldwide shortage of pancreatic donors remains a major challenge. In an attempt to expand the donor pool, pancreases from obese organs donors (>30 kg/m²) are now routinely offered to islet transplantation in the UK. In addition, it has been suggested that pancreases from donors with early type-2 diabetes mellitus may also be suitable. However, for both these donor groups, although high islet yields (IEQ) may be obtained, it is unclear whether these islets function optimally. An additional approach to the donor shortage is to minimise the number of donors required per islet recipient. One strategy to achieve this is to use different pharmacological agents to enhance post-transplant islet function. Aims: The aims of this thesis were fourfold; 1) To determine whether islets isolated from high BMI donors function normally in vitro and in vivo; 2) To establish why islet yields are higher from obese donors; 3) To determine whether islets from donors with type-2 diabetes are suitable for islet transplantation; 4) To investigate whether glucagon-like peptide 1 receptor agonist therapy improves post-transplant islet graft function. Results: Stimulated insulin and glucagon secretion, and markers of mitochondrial function (intra-islet ATP content and mitochondrial copy number) were compared in islets isolated from obese (BMI>30kg/m²; n= 27) and non-obese (BMI<28kg/m²; n=25) donors. No differences in secretory function or intra-islet ATP were observed between the two groups. Pancreatic lipid and intra-islet triglyceride concentrations were higher in the obese group. In vivo clinical outcomes of patients transplanted in Oxford and a larger cohort (n=35) in Edmonton, Canada with islets from obese or non-obese donors showed no differences in post-transplant outcomes. Improved islet yields were shown to be a result of improved islet recovery of larger islets, in obese donors. Abnormal insulin and glucagon secretory responses were observed in islets from type-2 diabetic subjects (n=6) and islet amyloid content was significantly higher in diabetes. The glucagon-like peptide 1 receptor agonist, exenatide, administered for 20 weeks, significantly improved graft function in patients whom islet function was impaired. Conclusion: The high lipid environment of islets isolated from donors with high BMI appears not to be deleterious to their function either in vitro or when transplanted, supporting the use of islets from high BMI donors for clinical islet transplantation. However, islet dysfunction and pathological changes indicate that islets from type-2 diabetic donors are unsuitable. Therapeutic options such as exenatide, improve transplanted islet viability and function, and could have a significant role in the future of beta-cell replacement therapy for type-1 diabetes.
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