Background: When a child suffers from chronic illness, it affects the whole family. Type 1 diabetes in children is becoming more common and over 900 children in Sweden per year suffer from the disease. Self-care becomes a fact and parents have the greatest responsibility for nursing. There will be major changes in life and previous routines changed to new ones. The nurse has an important responsibility in supporting and guiding the parents in an individualized and appropriate manner. Aim: The purpose of this literature study was to elucidate parents' experience of living with a child with type 1 diabetes. Method: The method used was a literature-based study based on qualitative studies. Nine qualitative articles were analyzed according to Friberg's five-step model. Results: The result is presented in two themes as; When life changes and New challenges. When life changed, three sub-themes meant describing the parents' experience of the changed life situation. New challenges with three subthemes focus on the parents 'experience of balancing the parent's perspective with the carers' perspective. Conclusion: Understanding the parents 'experience of living with a child with type 1 diabetes can help the nurse meet the parents' nursing needs by taking the responsibility of nursing and using their core competencies.

SAMMANFATTNING Bakgrund: Typ 1-diabetes är den vanligaste metabola sjukdomen hos barn och utgången är dödlig utan behandling. Behandlingen består av livslång insulintillförsel i kombination med blodsockerkontroll, kostberäkning och fysisk aktivitet. Trots utveckling av behandlingsregimen vid typ 1-diabetes finns det kvarstående betydande risker för långtidskomplikationer och psykisk ohälsa hos barnen som lever med sjukdomen. Familjerna och barnen utsätts för dagliga utmaningar samt den påfrestning det innebär att leva med en kronisk sjukdom. Syfte: Att undersöka hur barn med typ 1-diabetes upplever sin sjukdom samt hur de upplever att typ 1-diabetes påverkar deras liv. Metod: En systematisk litteraturstudie med induktiv design tillämpades. Sökningarna genomfördes i PubMed, CINAHL och PsycInfo och resulterade i 16 inkluderade vetenskapliga studier med kvalitativ ansats. Resultat: Barnens upplevelser av diabetes var framför allt negativa och mestadels kopplade till egenvården, som var tidskrävande, störande och smärtsam för barnen. Många barn hade blivit utsatta för stigmatisering, utanförskap och mobbning. Rädslan för att bli behandlad annorlunda av omgivningen gjorde att barnen ofta hemlighöll sin diabetes och i vissa fall struntade i behandlingen, särskilt i skolmiljön, som upplevdes dåligt anpassad efter barnens behov. Slutsats: Typ 1-diabetes påverkar barnen emotionellt och i synnerhet socialt där den mest utmanande tiden var i skolan. Barnsjuksköterskor har som ansvar att utefter barns behov stötta egenvård och självständighet och därigenom underlätta så att sjukdomen blir en del av livet för barnen.

Die Studie des menschlichen T1D (Type 1 Diabetes), als eine Autoimmunerkrankung der Bauchspeicheldrüse, könnte man mit der Entdeckung von Insulin unter Verwendung von pankreatectomisierten Tieren argumentieren. Es folgten Studien zur Verfeinerung des Insulinersatzes, Verbesserung der Technologien und zur Untersuchung von Stoffwechsel- und Autoimmunphänomenen in Blutproben. Während Tiermodelle eine Endorgananalyse erlaubten, war die Untersuchung der menschlichen Bauchspeicheldrüse im Vergleich zu Studien mit peripherem Blut stark eingeschränkt. Anhand der so genannten peripheren Blutstudien, die nPOD (Network for Pancreatic Organ Donors with Diabetes), konnte eine menschliche Bauchspeicheldrüsenbank mit Proben von Personen zusammenzustellt werden, die durch die Analyse peripherer Blut-Autoantikörper (Wasserfall, et al., 2016) für T1D als risikoreich eingestuft wurde [CW 1]. Das Hauptziel meiner Dissertation bestand darin, mit diesen noch immer ansteigenden Proben, einige grundlegende Fragen der menschlichen T1D-Biologie zu beantworten. Zuerst konnten meine Kollegen und ich Insulitis bei Autoantikörper-positiven Probanden und bei Patienten mit T1D-Diagnose (Campbell-Thompson, et al., 2016a) studieren [CW 2]. Dabei fanden wir in 2 von 5 Pankreasproben Insulitis von Autoantikörper-positiven Probanden, beide mit der Kombination GADA und IA-2A. In Pankreasproben von T1D-Spendern mit weniger als einem Jahr Krankheitsdauer hatten 100% der Patienten eine Insulitis. Während, in denen mit mehr als einem Jahr Krankheitsdauer, 23% der Insulitis aufzeigten. Dies impliziert, dass die Insulitis vorwiegend zum Krankheitsbeginn auftritt und danach abnimmt. Das steht im extremen Gegensatz zum NOD-Mausmodell, bei dem Insulitis sehr früh auftritt und bei 100% der Inzuchtmäuse, unabhängig davon, ob sie T1D entwickeln oder nicht. Auch im Gegensatz zum NOD, während β-Zellmasse in T1D-Pankreasproben reduziert wurde, fehlte es nicht ganz. Wir bestätigten ebenfalls die Ergebnisse einer reduzierten Gesamtmasse menschlicher T1D-Pankreasproben, die nicht durch fehlende β-Zellen erklärt werden, da die nur einen kleinen Teil des Organs ausmachen. Dies impliziert den Verlust von exokrinem Gewebe in einer Art und Weise, die bis heute ungeklärt bleibt. Weiterhin haben wir getestet, ob Komplement eine potenzielle Rolle in T1D spielt, indem die C4d-Deposition als Marker für (Auto) Antikörpervermittelte Ereignisse verwendet wurde (Rowe, et al., 2013) [CW 3]. Unerwarteterweise fanden wir heraus, dass es erhöhte C4d Antikörperfärbung in T1D Pankreasproben gab. Dies implizierte die Verteilung potentieller exokriner Entzündungen und nicht unbedingt Insel-spezifische Ereignisse. Ob dies mit den Befunden der kleineren Bauchspeicheldrüse in T1D zusammenhängt, ist eine naheliegende Frage für zukünftige Studien. Bei der Zusammenstellung dieser Begriffe verwendete ich eine Technik, um Proteine aus gefrorenen Abschnitten der Bauchspeicheldrüse zu extrahieren und fand die Persistenz von Proinsulin, während die Insulin- und C-Peptid-Konzentrationen niedrig bis nicht nachweisbar durch ELISA in T1D-Proben waren (Wasserfall, et al., 2017) [CW 4]. Weiterhin konnten wir zeigen, dass INS mRNA durch ISH und RT-qPCR zusammen mit Proinsulin und Insulin durch Immunhistochemie anwesend war. Wir waren ebenfalls in der Lage, die Progression von T1D semi-quantifizieren, durch den Verlust von Insulin in Inselchen, sondern die Persistenz von Insulin-positiven Einzelzellen mit längerer Krankheitsdauer. Das Enzym PCSK1 wurde außerdem in T1D-Proben durch RT-qPCR reduziert, was auf einen möglichen Mechanismus für die unvollständige Verarbeitung von Proinsulin zu reifem Insulin und CPeptid hindeutet. Die Aufklärung dieses Prozesses und die Frage, ob die einzelnen insulinpositiven Zellen als therapeutische Option gerettet werden können oder ob sie die Zellen von β dedifferenzieren, werden in Zukunft weiterverfolgt.:TABLE OF CONTENTS II LIST OF ABBREVIATIONS IV LIST OF FIGURES V SUMMARY 1 1 MOTIVATION 1 2 STATE OF THE ART 6 2.1 Type 1 diabetes is an autoimmune disease 6 2.2 Models of type 1 diabetes 6 2.3 Humoral immune responses in type 1 diabetes 7 2.4 Genetics and Cell mediated immunity in type 1 diabetes 8 2.5 The lesion in type 1 diabetes 11 2.6 Prediction of type 1 diabetes in the general human population 14 3 OBJECTIVES 17 4 OWN RESEARCH RESULTS 19 4.1 Screening organ donors for type 1 diabetes autoantibodies is feasible 19 4.2 The insulitis lesion in humans reveals the heterogeneity of type 1 diabetes 20 4.3 Complement deposition in the human pancreas is not specific to islet blood vessels 22 4.4 The pancreas of individuals with type 1 diabetes shows progressive loss of insulin, but proinsulin persists 22 5 DISCUSSION 26 5.1 Even with a low prevalence disease such as T1D it is possible to screen organ donors for the presence of disease specific autoantibodies 26 5.2 Insulitis in the natural history of T1D 26 5.3 Complement deposition in the natural history of T1D 28 5.4 Presence of endocrine hormones in the natural history of T1D 29 6 RESUME 31 SUMMARY GERMAN 33 BIBLIOGRAPHY 35 LIST OF PUBLICATIONS 53 [CW1] Validation of a rapid type 1 diabetes screening assay for community-based screening of organ donors to identify subjects at increased risk for the disease 54 [CW2] Insulitis and β-Cell Mass in the Natural History of Type 1 Diabetes 66 [CW3] Increased Complement Activation in Human Type 1 Diabetes Pancreata 82 [CW4] Persistence of Pancreatic Insulin mRNA Expression and Proinsulin Protein in Type 1 Diabetes Pancreata 87 CURRICULUM VITAE 101 ACKNOWLEDGEMENTS 121 SELBSTSTÄNDIGKEITSERKLÄRUNG 124 ANLAGE 1 125 ANLAGE 2 127

Type 1 Diabetes (T1D) is an autoimmune disease characterized by islet -specific T cells that infiltrate the pancreas and destroy the β-cells, crippling the necessary supply of insulin to control blood glucose levels. Although the disease can be managed by blood glucose monitoring, insulin injections and strict dietary regimens, there is currently no cure and complications continue to cause significant morbidity and mortality. Immunotherapies designed to inhibit islet-specific T cells are an attractive approach to treat T1D. Antibodies blocking the Interleukin-7/Interleukin-7 Receptor α (IL-7/IL-7Rα) pathway, which is critical for naïve and memory T cell survival, have shown promise in the non-obese diabetic (NOD) mouse model. Systemic administration of anti-IL-7Rα antibodies have prevented and reversed T1D in these models. However, hyperglycemia returned upon cessation of treatment, indicating no durable tolerance was established. Because of these results, I sought to better understand the mechanisms underlying the impact of IL-7Rα blockade on conventional islet-specific T cells and regulatory T cells (Tregs). I hypothesized that IL-7 signaling blockade (1) altered metabolism leading to impaired diabetogenic T cell effector functions and (2) impaired Tregs in peripheral tissues, potentially diminishing the therapeutic activity of anti-IL-7Rα antibodies. The data show that IL-7 signaling blockade impaired mitochondrial respiration independent of calcium signaling and downstream proteins. Impaired respiration shifted T cells to a more inefficient metabolic state. These inefficiencies were associated with diminished pro-inflammatory cytokine production. The cell-intrinsic role of IL-7 signaling in Tregs was assessed by crossing floxed IL-7Rα NOD mice with NOD mice that expressed Cre recombinase exclusively in Foxp3+ Tregs. At the onset of T1D IL-7Rα-deficient Tregs presented in lower frequencies than IL-7Rα-sufficient Tregs in pancreatic lymph nodes, and expressed higher levels of the co-inhibitory receptors PD-1 and TIGIT, indicating a more exhausted phenotype. Importantly, NOD mice with IL-7Rα-deficient Tregs developed T1D earlier. The data presented herein show that IL-7 signaling regulates T cell mitochondrial metabolism, T cell effector function, and identifies a role for IL-7 in the survival and function of Tregs in peripheral tissues during T1D development. This work simultaneously validates the IL-7 pathway as a potential immunotherapeutic target to modulate islet-specific T cells and cautions that unintended effects on protective Tregs must be taken into account for therapeutic strategies.

Eating Disorder-Diabetes Mellitus Type 1 (ED-DMT1) refers to individuals who have type 1 diabetes and a co-occurring eating disorder. The aim of this study was to identify current treatment practices for individuals with ED-DMT1 in a residential eating disorder treatment setting. Clinical nutrition managers (CNMs) at 18 residential eating disorder treatment facilities were interviewed about treatment practices for patients with type 1 diabetes. Four themes were identified through qualitative case study analysis: 1) nutrition interventions for patients with diabetes, 2) medical diabetes management, 3) interdisciplinary diabetes team, and 4) CNM's assessment of diabetes care. The majority of CNMs interviewed reported utilizing an exchange- based meal plan, which is well suited for patients with type 1 diabetes. Dietitians described the use of diabetes technology (e.g., insulin pumps and continuous glucose monitors) and described a gradual advancement of responsibility and autonomy with portioning food at meals and snacks and managing diabetes care. The dietitian is heavily involved in providing diabetes education along with the medical and/or nursing team. The majority of CNMs interviewed demonstrated knowledge deficits related to diabetes management and expressed the need and desire for increased education for themselves and other staff members in order to provide the highest quality of care.

Baroreflex sensitivity is impaired by diabetes mellitus. Previously, we found that diabetes induces a deficit of central mediation of baroreflex-mediated bradycardia. In this study, we assessed whether diabetes induces degeneration of the nucleus ambiguus (NA) and reduces heart rate (HR) responses to l-Glutamate (L-Glu) microinjection into the NA. FVB control and OVE26 diabetic mice (5-6 months) were anesthetized. Different doses of L-Glu (0.1-5 mM/l, 20 nl) were delivered into the left NA using a multi-channel injector. In other animals, the left vagus was electrically stimulated at 1-40 Hz (1 ms, 0.5 mA, 20 s). HR and mean arterial blood pressure (MAP) responses to L-Glu microinjections into the NA and to the electrical stimulation of the vagus were measured. The NA region was defined by tracer TMR-D injection into the ipsilateral nodose ganglion to retrogradely label vagal motoneurons in the NA. Brainstem slices at - 600, - 300, 0, + 300, and + 600 μm relative to the obex were processed using Nissl staining and the number of NA motoneurons was counted. Compared with FVB control, we found in OVE26 mice that: 1) HR responses to L-Glu injection into the NA at doses of 0.2-0.4 (mM/l, 20 nl) were attenuated (p < 0.05), but MAP responses were unchanged (p > 0.05). 2) HR responses to vagal stimulation were increased (p < 0.05). 3) The total number of NA (left and right) motoneurons was reduced (p < 0.05). Taken together, we concluded that diabetes reduces NA control of HR and induces degeneration of NA motoneurons. Degeneration of NA cardiac motoneurons may contribute to impairment of reflex-bradycardia in OVE26 diabetic mice.

Bakgrund: Typ 1 diabetes mellitus (T1DM) bland ungdomar ökar i Europa och också i Sverige. Sjukdomen är kronisk och kräver livsstilsförändringar samt egenvård. Ungdomsåren kännetecknas av frigörelse från föräldrar och att hitta sin sociala tillhörighet. Att drabbas av kronisk sjukdom under denna del av livet kan antas vara särskilt omvälvande. Syfte: Syftet var att beskriva ungdomars upplevelser av att leva med T1DM. Metod: Studien var baserad på en litteraturöversikt med tio vetenskapliga artiklar som systematiskt söktes fram från databaserna Cinahl Complete och PubMed. Analysen genomfördes enligt fem steg där sista steget bestod av kategorisering och tematisering av artiklarnas resultat. Resultat: Genom analysen identifierades tre teman; Ett liv som ungdom med T1DM i isolering och utanförskap, mötet med sjukvårdspersonal, upplevelser av diagnostiseringen. Slutsats: Litteraturöversikten visar att ungdomarna hade svårigheter att hantera den förändrade livssituationen efter diagnosen. De beskriver känslor av utanförskap och isolering. Ungdomarnas kontakter med vården är överlag negativ då de inte blir respekterade som individer. Resultatet diskuteras med utgångspunkt från Dorotea Orems egenvårdsteori. / Background: Type 1 diabetes mellitus (T1DM) among young people is increasing in Europe and also in Sweden. The disease is chronic and requires lifestyle changes and selfcare. Adolescence is characterized by liberation from parents and finding one’s social affiliation. Suffering from a chronic illness during this part of life can assumed to be particularly transformative. Aim: The aim was to describe young people’s experiences of living with type 1 diabetes mellitus. Method: The study was based on a literature review with ten scientific articles systematically retrieved from the databases Cinahl Complete and PubMed. The analysis was carried out according to five steps, the last step consisted of categorizing and thematizationthe results from the included articles. Results: The analysis resulted in three themes: A life as a youth in isolation and exclusiondue to T1DM, encounters with healthcare professionals and Experiences of getting thediagnosis. Conclusion: This literature review highlights that young people had difficulty coping with the changed life situation after the diagnosis. They described feelings of exclusion and isolation. Their contacts with healthcare are generally perceived as negative as they experienced not being respected as individuals. The results are discussed in relation to Dorotea Orem’s self-care theory.

Bakgrund: Diabetes typ 1 är en av de vanligaste förekommande folksjukdomarna i Sverige. För personer i ungdomsåren med diabetes typ 1 äger en transition från barn till vuxen hälso- och sjukvård rum vid någon punkt i dess liv. Transitionen är en övergång från en fas i livet till en annan och är en viktig del av ens liv som inte alltid är enkel även om strävan mot anpassning är önskvärd. Syfte: Syftet med litteraturstudien är att utifrån barn diagnostiserade med diabetes typ 1 kartlägga upplevelser av transitionen från barn till vuxen hälso- och sjukvård.Metod: En kvalitativ litteraturstudie baserad på 11 vetenskapliga studier från databaserna CINAHL, Psycinfo och PubMed. De vetenskapliga studierna lästes igenom och relevansgranskades utifrån inklusions och exlusionskriterierna för att sedan kvalitetsgranskas och sammanfattas i en metasyntes. Resultat: Resultatet visar att barn upplevde såväl oro som ivrighet inför sitt ökade egenansvar. De upplevde oväntade skillnader mellan hälso- och sjukvården för barn och vuxna. Inför transitionen ansåg de sig ha fått bristfällig information om dess innebörd för dem som personer och för deras sjukdom. De uttryckte även en förbättringspotential gällande transitionen. Konklusion: Litteraturstudien kartlägger hur barn diagnostiserade med diabetes upplever transitionen från barn till vuxen hälso- och sjukvård. Transitionen är en tidsperiod förknippad med oro och rädsla inför en förändrad framtid vilket barn upplever sig otillräckligt förberedda inför och informerade om. Således en tidsperiod då de inte vet vad de kan förvänta sig vilket upplevs skrämmande. / Background: Type 1 diabetes is one of the most common endemic diseases in Sweden. Children with type 1 diabetes will go through a transition from child- to adult healthcare. This transition is a shift from a part of the child’s life to another and is an important part of life that is not effortless even if the strive towards adaption is wanted. Purpose: The purpose of this literary study is to map experiences of children diagnosed with type 1 diabetes and transitioning from child- to adult diabetes healthcare.Method: A qualitative literary study was conducted, in which eleven scientific articles from the relevant databases; CINAHL, Psycinfo and PubMed were included. The studies were read, scrutinized and evaluated in relation to the inclusion- and exclusion criteria, followed by a qualitative review to merge the qualities of the studies to a meta-synthesizes. Results: The results show that children’s experience anxieties as well as eagerness for more self-responsibility. They experienced unexpected differences between child- and adult healthcare, in addition to the information given before the transition was inadequate regarding the affects for them and their sickness. The children expressed their wishes for a good transition.Conclusion: This literary study charts experiences from children with type 1 diabetes who transition from child- to adult healthcare. The transition is a period that comprise anxieties and fear for a changed future. Children with type 1 diabetes often experienced mostly insufficient preparations for the transition and the information given. Furthermore, they experienced the transition as frightening since they had no idea of what to expect.

Indiana University-Purdue University Indianapolis (IUPUI) / Oxidative stress can disrupt cellular homeostasis, leading to cellular dysfunction and apoptosis. The Nrf2 transcription factor regulates the antioxidant response in cells by binding to antioxidant response elements (ARE) in DNA and activating genes of enzymes that combat oxidative stress. During the pathogenesis of diabetes mellitus (DM), β-cells are exposed to increased amounts of reactive oxygen species (ROS) that cause oxidative stress. Zebrafish (ZF) are excellent models for studying the dynamic mechanisms associated with DM pathogenesis, and we recently developed a ZF model of β-cell apoptosis caused by ROS. Two paralogs of Nrf2 have been identified in ZF, Nrf2a and Nrf2b, but their roles in pancreas development and/or β-cell survival are unknown. To investigate their roles, Nrf2a and Nrf2b antisense morpholinos (MO) were injected into Day 0 ZF embryos and analyzed over time. While Nrf2a MO showed no obvious phenotypes compared to WT, Nrf2b MO exhibited reduced pancreas size and islets with disrupted morphology. Ins:NTR Nrf2a MO showed reduced β-cell loss upon exposure to Metronidazole (MTZ) under generation of ROS compared to WT. Sequence analysis of ZF nrf2b in 3-day post-fertilization (dpf) embryos revealed a novel splice variant containing an additional exon that has not been described. Further investigation of Nrf2a and Nrf2b is likely to yield additional insights regarding the function and regulation of the NRF2-signaling pathway and their roles in β-cell protection under oxidative stress.

No description available.