Background: Vaccines have been hypothesized in the etiology of autoimmune diseases including type 1 diabetes. There are cases of diabetes reported in the Vaccine Adverse Event Reporting System (VAERS) following the administration of the human papillomavirus (HPV) vaccine, however this potential association has yet to be investigated. The objective of this thesis was to determine whether there is an association between immunization against HPV and the development of type 1 diabetes mellitus in grade 8 girls eligible for Ontario’s vaccination program. Methods: A retrospective, population-based, cohort study of girls residing within an Ontario health unit and eligible for the province’s publicly funded school-based HPV vaccination program between 2007 and 2010 was executed using provincial administrative health databases and the Immunization Recording Information System (IRIS) database. To control for known, unknown and unmeasured time-independent confounders, a self-controlled case series analysis was conducted. The relative incidence and 95% confidence interval were estimated using conditional Poisson regression. Results: The study cohort was comprised of 3465 girls with a mean age of 13.2 years at cohort entry (range 12.7 to 13.6 years). The mean duration of follow up was 2.7 years and ranged from 1.6 to 3.6 years. The proportion of girls who received at least one dose of the qHPV vaccine during the observation period was 58.3% (n=2020). During the study follow-up 15 cases of new onset type 1 diabetes were observed, six of which were classified as etiologically exposed to the qHPV vaccine. Using an indefinite risk window, immunization with the qHPV vaccine was not associated with an increased risk of developing type 1 diabetes (age and season-adjusted RI 0.15; 95% CI 0.02-1.32). Conclusions: The results of this thesis regarding the risk of type 1 diabetes following immunization with the qHPV vaccine are inconclusive as a consequence of the small number of cases identified. However, the random distribution of cases across time and across exposure status suggests that there is no association. Before a definitive conclusion is reached the analysis must be re-conducted on a larger cohort. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2012-05-28 10:39:00.73

Type 1 diabetes (T1D) is an autoimmune disease that occurs when T lymphocyte cells attack and destroy beta cells in the pancreas.1 The cause of T1D is considered to be a combination of genetic predisposition and environmental or lifestyle risk factors. Early introduction of diet is thought to play a role in the development of T1D as it is less common in people who were breastfed and who were introduced to solid foods at later ages. The protection that breastfeeding can offer against the development of childhood obesity and T1D in children at risk for T1D is unknown and may be related to many different factors. The purpose of this project is to review the literature on the association between infant diet, including breastfeeding and complementary foods, and the development of obesity and T1D. This information will be used to prepare a secondary analysis proposal to examine the association between length of exclusive breastfeeding and obesity risk in children at risk for T1D for submission to the Presentations and Publications Committee of the Trial to Reduce IDDM in the Genetically at Risk (TRIGR) study.

Indiana University-Purdue University Indianapolis (IUPUI) / Bone disease and degradation is a ubiquitous problem, the complexity and treatment of which humanity has only begun to understand. Diabetes Mellitus is a disease which, in all forms, profoundly effects the organs of the body, bone included. As is often the case in biology, there are inherent differences between the sexes when considering skeletal development and disease progression and outcome. Although there are several reported mouse models for diabetes, until now there has been no characterization of bone disease in any model where diabetes occurs with equal frequency in males and females in greater than 90% of animals. In this study, a protocol for reliable induction of diabetes in both sexes using intraperitoneal injections of Streptozotocin was developed. The resulting bone phenotype in male and female mice was characterized and compared to weight and age matched control groups. In this model female diabetic mice exhibited a robust deficit in bone quality, while both sexes experienced loss of beta-cell mass and increased glycation of hemoglobin rendering the diabetic mice unable to produce insulin endogenously. Further, these mice were unable to metabolize exogenous insulin injected during insulin tolerance testing. This model is a strong candidate for future exploration of osteoporotic bone disease, Diabetes Mellitus, and the link between estrogen and glucose sensitivity.

Several epidemiological and clinical studies have indicated a possible role of Enterovirus (EV) infection in type 1 diabetes (T1D) development. However, the exact casual mechanism of these viruses in T1D development is not known. The aim of this thesis is to study various EVs that have been shown to differ in their immune phenotype, lytic ability, association with induction of islet autoantibodies, ability to replicate, cause islet disintegration and induce innate antiviral pathways in infected pancreatic cells in vitro. Furthermore, EV presence and pathogenic process in pancreatic tissue and isolated islets of T1D patients was also studied. Studies in this thesis for first time show the detection of EV RNA and protein in recent onset live T1D patients supporting the EV hypothesis in T1D development. Further all EV serotypes studied were able to replicate in islets, causing variable amount of islet disintegration ranging from extensive islet disintegration to not affecting islet morphology at all. However, one of the EV serotype replicated in only two out of seven donors infected, highlighting the importance of individual variation between donors. Further, this serotype impaired the insulin response to glucose stimulation without causing any visible islet disintegration, suggesting that this serotype might impaired the insulin response by inducing a functional block. Infection of human islets with the EV serotypes that are differentially associated with the development of islet autoantibodies showed the islet cell disintegration that is comparable with their degree of islet autoantibody seroconversion. Suggesting that the extent of the epidemic-associated islet autoantibody induction may depend on the ability of the viral serotypes to damage islet cells. Furthermore, one of the EV strains showed unique ability to infect and replicate both in endo and exocrine cells of the pancreas. EV replication in both endo and exocrine cells affected the genes involved in innate and antiviral pathways and induction of certain genes with important antiviral activity significantly varied between different donors. Suggesting that the same EV infection could result in different outcome in different individuals. Finally, we compared the results obtained by lytic and non lytic EV strains in vitro with the findings reported in fulminant and slowly progressing autoimmune T1D and found some similarities. In conclusion the results presented in this thesis further support the role of EV in T1D development and provide more insights regarding viral and host variation.  This will improve our understanding of the possible causative mechanism by EV in T1D development.

Type 1 diabetes is a condition which affects the lives of thousands of young people throughout the UK. Existing research has recognised the difficulties that adolescents have in managing their diabetes, and a large amount of research has focused on glycaemic control, and influential factors. This project attempted to establish what is known about young people’s experiences of living with type 1 diabetes, and to further develop this knowledge pertaining particularly to the school environment through qualitative research. Method A systematic review of the literature in relation to young people’s views of their life with type 1 diabetes was conducted and a synthesising thematic analysis was carried out. A qualitative research study was then carried out involving 7 adolescents aged 13-16 years who had a diagnosis of type 1 diabetes. Semi-structured interviews were carried out with the focus being on the young people’s experiences of type 1 diabetes within the school environment. Interview sessions were transcribed and Interpretative Phenomenological Analysis (IPA) was used to analyse the data. Results Five themes emerged from the systematic review. Analysis of the studies led to the emerging themes of: Normal/Different, Control/Management, Relationships, Health– care and Educational experiences. The articles revealed that the experiences of adolescents varied, and were frequently dependent upon the actions of others. Four major themes emerged from the analysis of the research study: Support, Knowledge and Understanding, Standing out, and Adjusting and Accepting. Discussion Systematic review of the articles revealed that the experiences of adolescents varied, and were frequently dependent upon the actions of others. A sense of normalcy was important, and the strict routine and activities of diabetes management impacted upon their ability to achieve it. The support of friends and family was valued, but could at times become overwhelming and educational and health professionals made a difference to their ability to successfully fit diabetes into their lives. The suggestions made by individuals within the studies were generally consistent, and have implications for healthcare providers, friends and families, and schools in relation to facilitating successful diabetic management. Many of the young people taking part in the present research study had encountered negative experiences within the school environment in relation to both peers and staff. However, they described elements of helpful practice and made suggestions for improvements that could be made within school to facilitate a more positive experience.

Due to psychosocial and hormonal changes, adolescents with Type 1 Diabetes (T1D) are at risk for poorer regimen adherence, quality of life (QOL), and glycemic control (HbA1c). Authoritative parenting (AP) supports youth development during the transition into adolescence. To date, the mechanisms behind authoritative parenting and better HbA1c are yet to be examined. Parent-youth dyads completed measures of authoritative parenting, adherence, and QOL. As hypothesized, more authoritative parenting related to higher socioeconomic status (SES; β = -.13, p = .04) rather than ethnicity. Further, more authoritative parenting related to better glycemic control via the mechanisms of higher youth QOL (β = .24, p < .001) and better diabetes adherence (β = .17, p = .008). Parents who provide more authoritative parenting have youth with better QOL, better adherence, and better glycemic control. More authoritative parenting helps youth achieve better diabetes care and quality of life during the transition into adolescence.

Background: Physical activity (PA) poses an additional burden on people living with type 1 diabetes (T1D) as it increases the risk of hypoglycemia, if performed at a moderate intensity. It is hypothesized that adding vigorous PA (VPA) into moderate PA (MPA) may help attenuate exercise-related hypoglycemia. Methods: Seventeen participants with T1D (23.7±6.6 years) completed an observational study of six days with continuous glucose monitoring and accelerometer-derived measures of PA to determine the association between PA intensity and both hypoglycemia risk and glucose variability (GV). Results: Higher evening moderate-to-vigorous PA (MVPA) increased the risk of overnight hypoglycemia (OR 1.03; 95% CI 1.002-1.047, p=0.031). Increased evening VPA was not associated with reduced hypoglycemia, but decreased overnight GV (3.20±0.25 for low vs 2.27±0.29 for high; p=0.022). Conclusions: Performing evening MVPA increases hypoglycemia risk overnight, but incorporating VPA did not prove to be protective. However, VPA reduced GV, which is a predictor of hypoglycemia. / May 2016

Type 1 Diabetes (T1D) is a serious chronic disease that results from an autoimmune destruction of the insulin-producing beta cells. Sweden has the second highest incidence of T1D in the world, and it affects more and more children each year. Genes controlling key functions of the immune system regulation of autoimmunity has been associated to T1D. Polymorphism in the Human Leukocyte Antigen (HLA) Class II is a major risk determinant for T1D but also Cytotoxic T lymphocyte Antigen 4 (CTLA-4) polymorphism can affect predisposition. Immune responses towards Glutamic Acid Decarboxylase 65 (GAD65), Insulin, insulinoma-associated antigen 2 (IA-2) and Heat Shock protein 60 have all been implicated in T1D pathogenesis. We aimed to study the effect and role of CTLA-4 and HLA Class II in the T1D immunity. By focusing on the immune responses associated to T1D in healthy children with risk genotypes we aimed to study immunological effects of T1D risk. We found that HSP60-peptide induced a higher IFN- response in subjects with risk associated CTLA-4 +49GG allele while GAD65 induced IL-4 secretion was lower in risk subjects. Individuals with T1D neutral HLA showed higher IFN- responses to GAD65 than DR3-DQ2 and DR4-DQ8 positive children. We did also detect that T1D patients have reduced IFN- responses to GAD65 compared to healthy children. Interestingly, HLA and CTLA-4 risk genotype seem to reduce those responses to become similar to responses of T1D patients. We also found that CTLA-4 and HLA risk is associated to reduced percentages of lymphocytes expressing intracellular CTLA-4 in healthy children. In another study we recorded maintained levels of CTLA-4 and TGF- mRNA responsiveness to GAD65 in recent onset T1D patients receiving ECP treatment although clinical outcome was certainly limited. In conclusion, HLA Class II risk genes but also CTLA-4 +49A/G to some extent, influence CTLA-4 capacity and T1D protective antigen-specific responses in a manner that might explain the genes’ predisposing and pathogenic capability. / Varför har Sverige näst efter Finland världens högsta incidens av barndiabetes? Typ 1 diabetes (T1D) är vanligare i norra Europa och särskilt i de nordiska länderna. Genetisk profil, infektioner och andra miljöfaktorer påverkar en individs mottaglighet för T1D. Hittills är det dock okänt vad som till slut utlöser den process som leder till att aktiverade immunförsvarsceller ”byter sida” och förstör kroppens egna insulinproducerande celler i bukspottskörteln. Ett grundläggande problem utifrån immunförsvarets perspektiv är att kunna skilja mellan vän och fiende, dvs skilja skadliga bakterie- eller virusfragment från fragment som tillhör kroppen själv. För att lära sig vad som är vad, utbildas immunförsvarets dirigenter, T-cellerna (en sorts vita blodkroppar) i thymus-körteln. Där sorteras överreagerande celler bort och de som blir kvar skickas ut i kroppen för att hjälpa oss att hålla oss friska. En förutsättning för att cellerna ska kunna göra den här åtskillnaden är att de nedbrutna bakterie- och virusfragment i form av äggviteämnen, visas upp för andra vita blodkroppar. HLA klass II molekylen fungerar som en serveringsbricka och håller upp det som ätarceller hittat och brutit ned. Variationer i konstruktionskoden för HLA gör att risken för att utveckla T1D ökar eller minskar. Möjligen sker detta genom att de HLA-varianter som finns i 95 % av T1D patienter serverar äggviteämnen på ett sätt som immunförsvaret missförstår som farligt. Vissa virus har identiska sektioner med äggviteämnen i de insulinproducerande cellerna vilket gör att immunförsvaret skulle kunna missta betacellerna för virusinfekterade celler och attackera dem. Det har på senare år visat sig att utbildningssystemet i thymus inte fungerar perfekt, utan faktiskt släpper igenom en del överreagerande celler, som skulle kunna starta reaktioner mot kroppens egna celler. För att hindra detta utnyttjar immunförsvaret ett kontrollsystem bestående av regulatoriska signaler och T-celler (T-reg celler). Treg celler har till uppgift att hålla eventuella självreaktiva immunprocesser i schack och undervisa immunförsvaret att tolerera ofarliga äggviteämnen. Ett viktigt äggviteämne i detta kontrollsystem är CTLA-4. Det är en ytmarkör som finns i och på T-celler, och framförallt T-reg celler. CTLA-4 fungerar som en sorts tröskel, så det krävs en tillräckligt stark (=säker) hotsignal för att komma över denna tröskel så att immunförsvaret sen kan gå till attack. CTLA-4 aktivitet tros vara väldigt viktigt i de mekanismer som kan bromsa eller hejda utvecklingen av T1D. Dessa skyddande mekanismer är målet för en del av forskningen kring framtida behandlingar av T1D. Konstruktionskoden för CTLA-4 varierar något mellan olika personer. Några varianter har visat sig vara sammankopplade med ökad risk för T1D och andra sjukdomar där immunförsvaret överreagerar och angriper kroppens egna vävnader (så kallade autoimmuna sjukdomar). Tidigare studier har visat att immunförsvarets signalmolekyler, cytokiner, driver in systemet mot i huvudsak två olika profiler, Typ1 och Typ2. De här profilerna är en viktig del i den normala kampen mot virus och bakterier, men i vissa sjukdomar visas en övervikt av den ena eller den andra profilen. Typ1 är vanligare bland personer som utvecklar typ 1 diabetes, medan Typ2 verkar skydda. Både immunprofil och Treg celler går att spåra med hjälp av signaler som är karakteristiska för celltyperna. Populärt förfarande vid utredning av T1D-immunologi och genetik är att man antingen studerar signalerna inom immunförsvaret och dess inbördes förhållanden, eller att man studerar hur stor andel av individerna med en viss genvariant som utvecklar sjukdomen. Detta är förstås värdefull information, men det lämnar en kunskapslucka i relationen mellan gen och immunförsvar. Det som är unikt med vår forskning är att vi studerat just vad för effekt de genetiska förändringarna får på immunförsvaret och särskilt det immunreglerande proteinet CTLA-4. Vår hypotes är att genom att gruppera friska och sjuka individer för olika kända riskgener - och sedan studera deras immunreaktioner – så kan vi identifiera delar av den process som riskgenerna verkar genom. Vi har fokuserat vår forskning på att försöka ta reda på hur de olika varianterna i HLA och CTLA-4 påverkar immunförsvaret så att de insulinproducerande cellerna angrips. Vi har observerat att immunsvaret i individer med den sjukdomsassocierade varianten av CTLA-4 har en större övervikt mot typ 1 när det retas med ett särskilt äggviteämne som är intressant inom diabetesforskning. Vi kunde även observera att friska barn med HLA klass II risk att utveckla T1D reagerade med svagare Typ1 svar än barn med neutrala gener när deras celler retades med ett äggviteämne som verkar vara aktivt i sjukdomsmekanismen av T1D. Intressant nog verkar barn med HLA risk ha en responsprofil som liknar de barn som redan utvecklat T1D. Observationer från ett annat projekt visar tecken på att barn med både CTLA-4 och HLA risk har försämrad förmåga till att uppreglera tolerans. Cellernas depåer av äggviteämnet CTLA-4 som är en viktig aktör i den toleransprocessen, är lägre i friska barn med genetisk risk. Inom avhandlingen har vi dessutom studerat effekter på toleranssystemen efter behandling med en tidigare föreslagen terapikandidat vid T1D, fotoferes. Behandlingen som i princip gick ut på att en andel av de vita blodkropparna bestrålades med UV-ljus, hade begränsade kliniska resultat men vi kunde se att behandlingen verkade stödja toleranssystemen. Genom att studera centrala immunologiska mekanismer och gener starkt förknippade med T1D har vi kunnat observera interaktioner mellan dessa system. Om vi drar oss till minnes att 95% av individerna som utvecklar T1D har HLA risk, kan vi nära nog säga att HLA risk är nästintill en förutsättning för att senare utveckla sjukdom. Vi visar att friska barn med HLA risk har en försämrad kapacitet att motverka ett självreaktivt immunförsvar. Kan det alltså vara så att T1D föregås av en försämring av kontrollsystemen? Det är viktigt att fortsätta undersöka hur CTLA-4 och framförallt HLA påverkar immunförsvaret och vad det betyder för personer med riskvarianter av dessa gener. I framtiden kanske vår forskning leder till att vi blir bättre på att se vem som riskerar att bli sjuk och hur detta går till. Det är också av yttersta vikt att vi får en tydligare bild av hur dessa centrala toleransmekanismer verkar när vi utvärderar den möjliga effekten av det nu aktuella T1D-”vaccinet” Diamyd och andra kliniska terapiförsök.

Background Type 1 diabetes is a chronically disease that often occurs in early life. In every year around 77.000 children in the world is estimated with type 1 diabetes. When a child gets a chronically disease it affects the whole family, specially the parents who will be the child's caregiver. Aim The aim of this study was to describe parents experiences of living with a child with type 1 diabetes. Method A literature review was carried trough based on 10 qualitative scientific articles. The articles were analyzed and two main themes and seven subthemes emerged. Results All parents experienced that they needed some kind of support particularly early in their illness. They felt it was a big responsibility to take care of their child with diabetes and parents often felt anxiety and fear associated with the disease. Not having constant control over their child the parents experienced as a pain. Increased knowledge and experience contributed the parents to feel security and found it easier to manage their child's illness. Conclusion It's normal for parents of children with a chronical illness to experience different emotions such as anxiety, fear, control needs and guilt. Therefore it's important that health care focuses on supporting and educates parents in caring for their child with diabetes.

The purpose of this study was to examine the relationship between family functioning, health-related quality of life, and metabolic control in order to identify areas for intervention that can improve medical and psychosocial outcomes for children and adolescents with type 1 diabetes. Children (N = 45) ages 8-17, both male and female, with type 1 diabetes, along with one caregiver (parent or legal guardian) (N = 45) were asked to complete the Pediatric Quality of Life Inventory (PedsQL) generic and diabetes-specific form to assess health-related quality of life along with the Diabetes Family Behavior Checklist and the Family Relationship Index of the Family Environment Scale to assess family functioning. Recent Hemoglobin A1c (A1c) was obtained from the physician at their visit or by parent report to assess metabolic control. Results indicated a significant relationship with poorer metabolic control relating to poorer physical health-related quality of life, as reported by children. All reports indicated a significant correlation between metabolic control and both general and diabetes specific health-related quality of life. There was a significant relationship with mother’s educational level on the outcome variables; educational level was therefore used as a control variable in all regression analyses. Child-reported general family functioning accounted for a significant amount of variance in child reported general health-related quality of life. Parent score on the non-supportive scale for diabetes specific family functioning accounted for a significant amount of variance in parent reported general health-related quality of life and diabetes specific health-related quality of life for their child. Results demonstrated the importance of obtaining both child and parent perspectives on issues regarding general family functioning and health-related quality of life and diabetes specific family functioning and health-related quality of life. In addition, they illustrated the importance of assessing health-related quality of life for children with diabetes as opposed to merely looking at the physical effects.