O diabetes mellitus tipo 1 é uma doença metabólica, caracterizada pela desregulação glicêmica, que ocorre devido a um ataque autoimune. A insulinoterapia é o tratamento clássico para o DM1. Contudo, alguns pacientes que apresentam essa doença não respondem de forma eficiente a este tratamento e apresentam episódios frequentes de hipoglicemia severa e despercebida (pacientes hiperlábeis). Essas complicações comprometem de forma significativa a qualidade de vida dessas pessoas. O transplante de ilhotas é uma importante alternativa para o tratamento de pacientes hiperlábeis com DM1. No entanto, essa terapia apresenta restrições como a necessidade de mais de um doador por transplante e significativa morte das ilhotas devido ao estresse provocado pelo procedimento de isolamento, além da morte promovida pelo sistema imune do paciente nos primeiros momentos pós-transplante. A autofagia é um mecanismo de reciclagem de componentes citoplasmáticos que é fundamental para a homeostase celular. Em condições de estresse, este mecanismo é ativado acima do seu nível basal, promovendo a degradação de agregados proteicos e organelas defeituosas, evitando assim, danos celulares que comprometam a viabilidade da célula. Trabalhos realizados por nosso grupo têm mostrado a citoproteção que PRL promove em células-beta, reduzindo a apoptose induzida por citocinas pró-inflamatórias. Também demonstramos o papel essencial de HSPB1 na inibição de apoptose induzida por PRL após o tratamento com citocinas. Além disso, resultados recentes de nosso laboratório mostraram um aumento nos níveis de autofagia em células-beta após sua exposição a citocinas, bem como uma restauração a níveis normais na presença de PRL. Visando um melhor entendimento do papel da PRL na modulação da autofagia em células-beta, o objetivo desse projeto foi estudar se HSPB1 também é essencial no mecanismo de regulação da autofagia induzido por PRL.Para tal, fizemos experimentos em modelos de células-beta MIN6, MIN6 silenciadas para HSPB1 (MIN6-shHSPB1) e MIN6 com sequencia short hairpin aleatória (MIN6- SsC), medindo a morte celular através de ensaios de viabilidade, e ensaios de western blot para avaliar os níveis de marcadores de autofagia e fluxo autofágico (degradação de autofagossomos), tratando as células com citocinas, prolactina e indutores ou inibidores de autofagia. Os resultados mostraram que a modulação da autofagia ocasionada pela prolactina em células-beta se dá, em parte, através de HSPB1. O tratamento com prolactina foi capaz de inibir a morte celular induzida por citocinas, mesmo na presença de cloroquina, um bloqueador de autofagia, o que nos levou a concluir que a autofagia não é uma via envolvida na citoproteção de células beta induzida por PRL. Os resultados gerados nesse estudo contribuíram para uma melhor compreensão dos eventos moleculares induzidos por PRL em células-beta, e poderão permitir a inferência de novas abordagens que melhorem a citoproteção, cultura e transplante dessas células em pacientes com diabetes tipo 1. / Type 1 diabetes mellitus is a metabolic disease characterized by glycemic dysregulation, which occurs due to an autoimmune destruction of beta-cells. Insulin therapy is the gold standard treatment for DM1. However, some DM1 patients do not respond efficiently to this treatment and suffer frequent episodes of severe hypoglycemia unawareness. Since this complication jeopardizes the quality of life of these people, Islet transplantation is a therapeutic alternative indicated to treat these patients. However, besides the lack of enough organ donors, the loss of beta cells during both the isolation as well as the infusion of islets into the recipient induce a great estresse and thus a significant cell death is one of the drawbacks of this procedure. Autophagy is a mechanism of recycling cytoplasmic components and is essential for cellular homeostasis. Under estresse conditions, this mechanism is activated above basal levels, promoting the degradation of protein aggregates and defective organelles, thus avoiding cell damage that could compromise cell viability. Studies carried out by our group have shown not only that PRL promotes cytoprotection in beta-cells, reducing pro-inflammatory cytokines-induced apoptosis, but also that HSPB1 plays an essential role in this inhibition of apoptosis mediated by PRL after treatment with cytokines. Moreover, recent results from our laboratory showed an increase in autophagy levels in beta-cells after exposure to cytokines, as well as a restauration to normal levels in the presence of PRL. In order to better understand the role of PRL in the modulation of autophagy in these cells, the aim of this project is to study whether HSPB1 is also essential in the mechanism of autophagy regulation induced by PRL. Using MIN6 beta cell models where HSPB1 was silenced (MIN6-shHSPB1) or not (MIN6-SsC), we studied cell death by viability assays. Moreover, western blot assays were performed in order to assess levels of autophagy and autophagic flux markers in the cells.Our results showed that HSPB1 in one of the mediators of PRL-induced modulation of autophagy. Nevertheless, since hormonal treatment was still able to inhibit cytokinesinduced cell death even in the presence of chloroquin, an autophagy blocker, we conclude that autophagy is not a signaling pathway involved in PRl-induced beta-cell cytoprotection. Altogether, the results shown in this study may help to increase the knowledge of the molecular events induced by PRL in beta-cells, and may allow to infer new approaches to improve cytoprotection, culture and transplantation of these cells into type 1 diabetic patients.

Introdução: Diabetes tipo 1A(DM1A) é uma doença causada pela destruição autoimune das células beta. Em adição aos linfócitos T helper 1(Th1) e Th2, um subtipo específico de células T helper recentemente descrito, Th17, caracterizado pela produção da interleucina 17(IL-17A), IL-17F e IL-22, está também envolvido na imunidade adaptativa e autoimunidade, incluindo DM1A. A IL-23 tem função fundamental na expansão e sobrevivência das células Th17. A mesma é composta por 2 subunidades: a p19-específica (IL-23A) e a p40. Variantes dos genes IL-23A e de seu receptor (IL-23R) ou o aumento das concentrações séricas da IL-23 estão associados a várias doenças autoimunes, mas seus efeitos no DM1A não estão definidos. Com o intuito de avaliar a importância da IL-23 na patogênese do DM1A, as variantes dos genes IL23A e IL23R foram analisadas. Metodologia: A região codificadora e os regiões intrônicas proximais do gene IL23A, incluindo a região 5 proximal foram sequenciadas. Duas variantes do gene IL23A (rs2066808 e rs11171806) e duas do gene IL-23R (rs11209026 e rs10889677) foram também genotipadas. A amostra contou com 370 pacientes com DM1A e 314 indivíduos controles saudáveis. As medidas das concentrações séricas da IL-23 e os autoanticorpos pancreáticos e extra-pancreáticos foram determinados. Resultados: Nós observamos somente uma das seis variantes da IL-23 descritas nos bancos de dados (rs11171806 G>A localizada no exon 3) e descrevemos uma nova variante no gene IL-23A, que consistiu na substituição da citosina por timina na posição c.-403 (C>T) na região 5 proximal deste gene (encontrada em heterozigose em apenas uma paciente com DM1A, do sexo feminino, com 28 anos ao diagnóstico).Os alelos G dessas duas variantes estiveram em forte desequilíbrio de ligação (D\' = -0,825 para controles, p<2,0X10-6 e D\' = -0,902, p<2,0X10-17 para pacientes). Em consequência, a análise dos haplótipos destas variantes foi realizada. O haplótipo GG foi mais frequente nos controles (16.7%) do que nos pacientes com DM1A (9.5%), conferindo proteção à doença (pc = 0,0009, OR = 0,53) . A presença do haplótipo GG diferiu de acordo com a etnia no conjunto de pacientes e controles, sendo menor naqueles de etnia caucasóide (18%) em relação aos outros grupos (39%); p<0.0001. Entretanto, o efeito protetor da haplótipo GG foi independente da etnia. As duas variantes do gene IL23R (rs10889677 e rs11209026) tinham frequência alélica e genotípica semelhante entre pacientes com DM1A e controles. Não foi observada diferença significante nas concentrações da IL-23 entre 135 pacientes com DM1A (5,65 ± 14,0 pg/mL) e 112 indivíduos controles (9,06 ± 23,7pg/mL) (p =0,18). , mesmo quando analisamos apenas o pacientes com duração do diabetes inferior a dois anos, nos quais a resposta imune contra as células beta ainda está presente, (4.65 ± 6.94 pg/mL e 9.07 ± 23.62 pg/mL, p = 0.076). Não foi encontrada associação entre as variantes do gene IL23A com a idade diagnóstica, presença do peptídeo C residual e auto-anticorpo anti-descarboxilase do ácido glutâmico em pacientes com diagnóstico recente de DM1A. Estas variantes também não influenciaram na freqüência dos auto anticorpos extrapancreáticos: anti-tireoglobulina, anti-peroxidase, anti-21 hidroxilase, fator anti-núcleo, fator reumatóide e anti-citoplasma de neutrófilos. Conclusões: O haplótipo GG das variantes do gene lL23A (rs11171806 e rs2066808) foi associado a proteção ao DM1A. As variantes do gene IL23R (rs11209026 e rs10889677) não foram associadas ao DM1A. As concentrações séricas da IL-23 foram semelhantes entre os grupos. / Introduction: Type 1 diabetes mellitus (T1D) is a disorder caused by the immune-mediated destruction of insulin-secreting pancreatic beta cells. In addition to T helper 1 (Th1) and Th2 cells, a recently discovered subset of T helper cells, Th17, characterized by the production of interleukin 17 A (IL-17A), IL-17F, and IL-22 is also involved in adaptive immunity and autoimmunity, including T1D. The Interleukin IL-23 has a central role in the expansion and survival of Th 17 cells. It is composed of two subunits: p19-specific (IL-23A) and p40. Single nucleotide polymorphisms (SNPs) of IL-23A and IL-23 receptor (IL-23R) genes or increased IL-23 serum concentrations were associated with several autoimmune diseases, but their role in T1D has not been defined. We therefore searched for variants of IL-23A and IL-23R genes that could predispose to T1D. Methods:The coding regions and boundary intron sequences of IL-23A gene, including the 5 proximal region were sequenced. Two variants (rs2066808 and rs 11171806) of IL-23A and two of IL-23R (rs11209026 and rs10889677) genes were also genotyped. IL-23 serum levels and pancreatic and extra-pancreatic auto-antibodies were also determined. The cohort involved 370 patients with T1D and 314 healthy control subjects.Results: We observed only 1 out of 6 IL-23A coding variants (rs11171806 G>A localized in exon 3) described in a database repository . A new allelic variant of the IL-23A gene, consisting of the substitution of a cytosine by a thymine at position c.-403 (C>T) in the 5 proximal region of the IL-23A gene (found in heterozygosis in only 1 female patient with T1D) was described. The G alleles of rs11171806 and rs2066808 variants of IL-23A gene were in strong linkage disequilibrium (D\' = -0,825 for controls, p<2,0X10-6 and D\' = -0,902, p<2,0X10-17 for patients). So, further analyses were performed with the haplotypes instead of separated SNPs. The GG haplotype was more frequent in controls (16,7%) than in T1D patients (9,5%), conferring a protection to the disease (pc= 0,0009, OR = 0.53). The presence of haplotype GG was also different according to the ethnic group in the overall sample (patients+controls), when we pooled the Caucasians (18%) against the other groups (39%); p<0.0001. However, the lower susceptibility to T1D conferred by GG haplotype was independent of the ethnic group. Two IL-23R gene variants (rs10889677 and rs11209026) were also analyzed. The allelic and genotypic frequency of the variants did not differ between patients with T1D and control subjects. No significant differences were observed between the plasma IL-23 concentrations of 135 T1D patients (5.65 ± 14.0) and 112 control subjects (9.06 ± 23.7) (p = 0.18), even when we only the patients with less than 2 years disease duration (n = 43), when the immune attack to beta cells is still present, were included (4.65 ± 6.94 pg/mL and 9.07 ± 23.62 pg/mL, p = 0.076). No association was found between IL-23A variants with age at diagnosis of diabetes, presence of residual C-peptide levels or frequency of glutamic acid anti-decarboxilase antibody in patients with recent-onset T1D. Furthermore, these variants were not related to the presence of the extrapancreatic autoantibodies such as thyroid peroxidase (TPO) Ab, thyroglobulin (TG) Ab, 21-Hydroxilase (21OH) Ab, Anti nuclear factor (ANA) Ab, rheumatoid factor (FR) Ab and Neutrophil cytoplasmic (ANCA) Ab. Conclusions : The GG haplotype of lL23A gene variants( rs11171806 and rs2066808) was protective against T1D. The IL23R variants (rs11209026 and rs10889677) were not associated with susceptibility toT1D . IL-23 serum concentrations did not differ between T1D patients and controls.

Background: There are significant psychological challenges faced by people throughout their lives and many of these challenges can be readily understood from a contextual behavioural science perspective, and Acceptance and Commitment Therapy (ACT) shows promise as a theoretically and practically relevant intervention. Some problems faced in delivering such an intervention are volume and access to healthcare. A potential solution to this is to design theoretically driven interventions which can be delivered through technology. These need to be interactive, individually shaped and will combine mindfulness, acceptance and values. Such interventions need to be evaluated scientifically according to acceptability, quality, safety and effectiveness. Aims: This thesis has two sections. Firstly, a systematic review aiming to assess the acceptability and effectiveness of using technology to deliver ACT. Secondly, an empirical research study aiming to analyse the experiences of using an ACT based app for young people with type 1 diabetes (TD1). Methods: The review searched 11 databases, and a related website. Included studies were required to use a form of technology to deliver ACT, with no real-time therapist. Two independent researchers determined inclusion of articles into the review and rated the studies according to the quality criteria. Where there was uncertainty a third reviewer was used. For the empirical study, individual interviews of 9 young people aged 13-22 years with TD1 were asked about their experiences of using the ACT based app. Framework analysis was used to determine themes. Results: The review search yielded 18 studies which met inclusion criteria. Findings highlighted that generally these interventions were seen as acceptable and satisfactory. All of these interventions were conducted in an adult population, and qualitative data was not robustly accounted for. The empirical research found two main themes: ‘Desire for apps to represent my needs’ and ‘How diabetes impacts me and how this could potentially be addressed in an app’. Discussion: Both the review and empirical study found that participants were positive about the use of technology to deliver ACT. Developmental progress needs to be made in the app to truly represent the needs of young people with TD1. These interventions could enhance the availability of psychological therapies. This has been highlighted as a government objective in several countries. Methodological weaknesses limit conclusions, such as underpowered studies. As this is a fast growing body of research it is hoped that future studies could be more similar methodologically. It would still be interesting to determine whether asynchronous contact enhances the cost-effectiveness of this form treatment. This thesis has provided me with the opportunity to design an ACT protocol for young people with type 1 diabetes (TD1). It has helped me to fully understand the undertaking which goes into designing apps and the scope of how responsive apps can be. It has given me the chance to communicate with people from different professional backgrounds to create a shared language, an opportunity to lead and manage a project and much more. With the help of my supervisor in my first year of training, we established links with the informatics department to see if students would be able to help with the programming of such an app. We had to create a synopsis of the proposed study to entice students to undertake the project as part of their degree. An interested student was assigned the project and meetings were held to determine our expectations and to establish the scope of what could be created. A second student took on the project during my second year or training. During this time my supervisor and I created a protocol of the content for the app. This was based on previous ACT protocols and tools we were aware of, which we thought might be helpful. A lot of thought had to go into trying to keep the content concise, including different modes of delivery (MP3s, video, animation etc), making the content applicable to young people with TD1 based on previous literature, and thinking about how interactive the app could be. Friends were also relied on to create graphics for the app. I went to different health boards across Scotland to meet with Diabetes teams to inform them about the project and to gather advice on the appropriateness of the diabetes information within the content of the app, and to determine whether they were interested in taking part in the study. I tested the initial prototype and glitches were ironed out. The next stage was to test the app on professionals working in the field, and to gather their feedback through focus groups. Adaptations to the app were made based on this. The app was initially made for Android phone devices based on general market research indicating that there was little evidence that one platform was more popular in adolescents. The diabetes teams and I tried to recruit young people with TD1 from their usual diabetes clinics. Initial barriers to recruitment were that at least 50% of young people had iPhones so could not download the app, and others did not seem interested in downloading the app to take part in the study. Funding of 10 Android tablets was agreed by the University. I attended the usual diabetes clinics in NHS Lothian and young people with TD1 started to volunteer to take part in the study. Originally it was hoped a trial of the effectiveness of the app would be carried out, but the difficulties in recruitment meant that instead I decided to use a qualitative methodology to explore young people’s experiences of using the app.

O diabetes mellitus tipo 1 é uma doença metabólica, caracterizada pela desregulação glicêmica, que ocorre devido a um ataque autoimune. A insulinoterapia é o tratamento clássico para o DM1. Contudo, alguns pacientes que apresentam essa doença não respondem de forma eficiente a este tratamento e apresentam episódios frequentes de hipoglicemia severa e despercebida (pacientes hiperlábeis). Essas complicações comprometem de forma significativa a qualidade de vida dessas pessoas. O transplante de ilhotas é uma importante alternativa para o tratamento de pacientes hiperlábeis com DM1. No entanto, essa terapia apresenta restrições como a necessidade de mais de um doador por transplante e significativa morte das ilhotas devido ao estresse provocado pelo procedimento de isolamento, além da morte promovida pelo sistema imune do paciente nos primeiros momentos pós-transplante. A autofagia é um mecanismo de reciclagem de componentes citoplasmáticos que é fundamental para a homeostase celular. Em condições de estresse, este mecanismo é ativado acima do seu nível basal, promovendo a degradação de agregados proteicos e organelas defeituosas, evitando assim, danos celulares que comprometam a viabilidade da célula. Trabalhos realizados por nosso grupo têm mostrado a citoproteção que PRL promove em células-beta, reduzindo a apoptose induzida por citocinas pró-inflamatórias. Também demonstramos o papel essencial de HSPB1 na inibição de apoptose induzida por PRL após o tratamento com citocinas. Além disso, resultados recentes de nosso laboratório mostraram um aumento nos níveis de autofagia em células-beta após sua exposição a citocinas, bem como uma restauração a níveis normais na presença de PRL. Visando um melhor entendimento do papel da PRL na modulação da autofagia em células-beta, o objetivo desse projeto foi estudar se HSPB1 também é essencial no mecanismo de regulação da autofagia induzido por PRL.Para tal, fizemos experimentos em modelos de células-beta MIN6, MIN6 silenciadas para HSPB1 (MIN6-shHSPB1) e MIN6 com sequencia short hairpin aleatória (MIN6- SsC), medindo a morte celular através de ensaios de viabilidade, e ensaios de western blot para avaliar os níveis de marcadores de autofagia e fluxo autofágico (degradação de autofagossomos), tratando as células com citocinas, prolactina e indutores ou inibidores de autofagia. Os resultados mostraram que a modulação da autofagia ocasionada pela prolactina em células-beta se dá, em parte, através de HSPB1. O tratamento com prolactina foi capaz de inibir a morte celular induzida por citocinas, mesmo na presença de cloroquina, um bloqueador de autofagia, o que nos levou a concluir que a autofagia não é uma via envolvida na citoproteção de células beta induzida por PRL. Os resultados gerados nesse estudo contribuíram para uma melhor compreensão dos eventos moleculares induzidos por PRL em células-beta, e poderão permitir a inferência de novas abordagens que melhorem a citoproteção, cultura e transplante dessas células em pacientes com diabetes tipo 1. / Type 1 diabetes mellitus is a metabolic disease characterized by glycemic dysregulation, which occurs due to an autoimmune destruction of beta-cells. Insulin therapy is the gold standard treatment for DM1. However, some DM1 patients do not respond efficiently to this treatment and suffer frequent episodes of severe hypoglycemia unawareness. Since this complication jeopardizes the quality of life of these people, Islet transplantation is a therapeutic alternative indicated to treat these patients. However, besides the lack of enough organ donors, the loss of beta cells during both the isolation as well as the infusion of islets into the recipient induce a great estresse and thus a significant cell death is one of the drawbacks of this procedure. Autophagy is a mechanism of recycling cytoplasmic components and is essential for cellular homeostasis. Under estresse conditions, this mechanism is activated above basal levels, promoting the degradation of protein aggregates and defective organelles, thus avoiding cell damage that could compromise cell viability. Studies carried out by our group have shown not only that PRL promotes cytoprotection in beta-cells, reducing pro-inflammatory cytokines-induced apoptosis, but also that HSPB1 plays an essential role in this inhibition of apoptosis mediated by PRL after treatment with cytokines. Moreover, recent results from our laboratory showed an increase in autophagy levels in beta-cells after exposure to cytokines, as well as a restauration to normal levels in the presence of PRL. In order to better understand the role of PRL in the modulation of autophagy in these cells, the aim of this project is to study whether HSPB1 is also essential in the mechanism of autophagy regulation induced by PRL. Using MIN6 beta cell models where HSPB1 was silenced (MIN6-shHSPB1) or not (MIN6-SsC), we studied cell death by viability assays. Moreover, western blot assays were performed in order to assess levels of autophagy and autophagic flux markers in the cells.Our results showed that HSPB1 in one of the mediators of PRL-induced modulation of autophagy. Nevertheless, since hormonal treatment was still able to inhibit cytokinesinduced cell death even in the presence of chloroquin, an autophagy blocker, we conclude that autophagy is not a signaling pathway involved in PRl-induced beta-cell cytoprotection. Altogether, the results shown in this study may help to increase the knowledge of the molecular events induced by PRL in beta-cells, and may allow to infer new approaches to improve cytoprotection, culture and transplantation of these cells into type 1 diabetic patients.

O diabetes melitus tipo 1 é caracterizado por hiperglicemia em decorrência da ausência de secreção de insulina, causada pela destruição de células beta do pâncreas, geralmente por alteração auto-imune. O objetivo deste estudo foi o de conhecer o perfil do paciente diabético tipo 1 em atendimento no CAPE FOUSP, relacionando as complicações as alterações sistêmicas e bucais do diabetes nestes pacientes. Foram coletados dados demográficos, dados da história médica [idade ao diagnóstico, histórico de crise de cetoacidose, hipoglicêmica e hiperglicêmica, maior e menor glicemia já registradas, presença de microangiopatias (retinopatia, doença renal, neuropatia) e macroangiopatias (doença cardiovascular, hipertensão arterial sistêmica), outras doenças sistêmicas, medicação em uso], realizado exame físico extra oral, com aferição da pressão arterial, exame físico intra-oral [para pesquisa de xerostomia, candidíase (pseudomembranosa, eritematosa, leucoplásica, queilite angular), GUNA úlcera aftosa recorrente, herpes simples, síndrome da boca ardente], índice CPOD, índice periodontal comunitário (ICP), índice gengival (IG), presença de cálculo, índice de placa, índice de maloclusão], exames complementares (avaliação do fluxo salivar, aferição da glicemia capilar e teste rápido de hemoglobina glicada) e o preenchimento do questionário Oral health impact profile (OHIP-14). Foram avaliados 26 pacientes, 11 do sexo masculino e 15 do sexo feminino, sendo que a média de idade do diagnóstico variou de 06 meses a 26 anos de idade, o tempo decorrente desde o diagnóstico variou de 1 a 37 anos, 61,53% dos pacientes apresentavam alguma microangiopatia e 27% dos pacientes alguma macroangiopatia. A manifestação bucal mais encontrada foi a xerostomia (61,53%), seguida da queilite angular (23,07%), a média do CPOD foi de 13,26, 50% dos pacientes apresentavam ICP escore 2 e os outros 50% apresentavam escore 3 e 4, 84,61% apresentavam gengivite moderada e a média do IP foi de 2,19. A maloclusão leve foi encontrada em 69% dos pacientes e 92,30% dos pacientes apresentavam fluxo salivar normal, 16 pacientes estavam com hiperglicemia, 23 pacientes apresentavam hemoglobina glicada descompensada e 58% dos pacientes apresentaram um impacto fraco de saúde bucal na qualidade de vida Concluímos que nossos pacientes com DM1 são jovens, com da glicemia e DM descompensados, apresentam a doença há mais de 10 anos, e desenvolveram microangiopatias e macroangiopatias como a doença renal e a hipertensão arterial. Apresentam poucas manifestações bucais, sendo a mais comum a xerostomia; e uma condição bucal satisfatória, em decorrência do acesso ao tratamento odontológico, independentemente da compensação da glicemia. / Diabetes mellitus type 1 is characterized by hyperglycemia due to the absence of insulin secretion caused by destruction of pancreatic beta cells, usually by autoimmune disease. The aim of this study was to establish the profile of the type 1 diabetic patients treated at CAPE FOUSP recognizing the systemic and oral complications of diabetes in these patients. We collected demographic data, medical history [age at diagnosis, history of ketoacidosis, hypoglycemic and hyperglycemic crisis, highest and lowest glycemia recorded, presence of microangiopathy (retinopathy, kidney disease, neuropathy) and macroangiopathy (cardiovascular disease, arterial hypertension), other systemic diseases, drugs in use], and performed blood pressure measurement, and extra and intra oral physical examination [searching for xerostomia, candidiasis (pseudomembranous, erythematous, leucoplakia, angular cheilitis), GUNA, aphthous ulcer, herpes simplex, burning mouth syndrome], DMFT index, community periodontal index (ICP), gingival index (GI), presence of calculus, plaque index, index of malocclusion], complementary tests (measurement of salivary flow and glycemia and a rapid test for glycated hemoglobin) and completing the questionnaire \" Oral health impact profile\" (OHIP - 14). We evaluated 26 patients, 11 males and 15 females, with age of diagnosis from 06 months to 26 years, time elapsed since diagnosis ranged from 1 to 37 years, 61.53 % presented with some microangiopathy and 27 % with macroangiopathy. The most frequent oral manifestation was xerostomia (61.53 %), followed by angular cheilitis (23.07%), the mean DMFT was 13.26, 50 % of patients had ICP score 2 and 50 % had score 3 and 4, 84.61% had moderate gingivitis and mean PI was 2.19. The slight malocclusion was found in 69 % of patients and 92.30 % of patients had normal salivary flow, 16 patients had hyperglycemia, 23 patients had glycated hemoglobin decompensated and 58 % of patients had a weak impact of oral health on quality of life. We conclude that our DM1 patients are young, with blood glucose and DM decompensated with diabetes for over 10 years, and developed microangiopathy and macroangiopathy like kidney disease and hypertension. Few patients have oral manifestations, and the most common is xerostomia, and a satisfactory oral health as a result of access to dental treatment, regardless of the rates of blood glucose.

Background: Each year approximately 700 children are affected by type 1 diabetes in Sweden. This chronic disease has an impact on the whole family but especially the parents who have the responsibility as a caregiver. Parents are therefore in need of support from friends and family as well as help from the nurse to deal with the situation. The nurse can provide support with a family focused care and will therefore include the whole family and use their strengths and resources. Aim: The aim of this study was to describe parents' experience of living with a child with type 1 diabetes. Method: The method used was a literature study with the aim to contribute to evidence based care with an analysis based on qualitative research. Ten scientific articles were analyzed. Three themes and seven subthemes emerged. Results: Three main themes and seven subthemes emerged during the analysis that responded to parents' experience living with a child with type 1 diabetes. The main themes were the stress that parents are exposed to, need of help and the unique community. Conclusion: Parents experienced a change in everyday life for the whole family. Therefore, the nurse needs to be responsive and adapt the nursing care to the parents, so they can support the child in a better way. / Studien beskriver föräldrars upplevelser av att leva med ett barn med typ 1 diabetes. Typ 1 diabetes är den mest förekommande autoimmuna sjukdomen hos barn i hela världen. Sjukdomen innebär att kroppen har slutat producera hormonet insulin, vilket medför en förhöjd blodsockernivå som kan leda till komplikationer. Studiens resultat baseras på tio vetenskapliga artiklar. Dessa söktes fram via två databaser. Genom analys och sammanställning av artiklarna framkom en beskrivning av föräldrarnas upplevelser. Detta redovisas som teman och subteman i resultatet. I resultatet beskrivs föräldrarnas omställning från att leva med ett friskt barn till att leva med ett barn med kronisk sjukdom och vilka känslor som uppstår vid bearbetningen samt det förändrade föräldraansvaret. Resultatet beskriver också de förhållanden som underlättar föräldrarnas bearbetning. Resultatet lyfter även fram de krav och förväntningar som föräldrarna har på vårdpersonal och personer i omgivningen samt den saknade förståelsen från människor runt föräldrarna.  Typ 1 diabetes påverkar barnens rätt att vara som andra och relationen med andra barn. Även relationen mellan barnet och föräldrarna påverkas. Sjukdomen drabbar inte bara barnet utan hela familjen. Sjuksköterskan är ansvarig för att ge familjen en god familjefokuserad vård och för att ge individanpassat stöd till föräldrarna i den förändrade livssituationen. Denna studie kan ge sjuksköterskor mer kännedom om vilka omvårdnadsbehov som föräldrarna har.

O diabetes melitus tipo 1 é caracterizado por hiperglicemia em decorrência da ausência de secreção de insulina, causada pela destruição de células beta do pâncreas, geralmente por alteração auto-imune. O objetivo deste estudo foi o de conhecer o perfil do paciente diabético tipo 1 em atendimento no CAPE FOUSP, relacionando as complicações as alterações sistêmicas e bucais do diabetes nestes pacientes. Foram coletados dados demográficos, dados da história médica [idade ao diagnóstico, histórico de crise de cetoacidose, hipoglicêmica e hiperglicêmica, maior e menor glicemia já registradas, presença de microangiopatias (retinopatia, doença renal, neuropatia) e macroangiopatias (doença cardiovascular, hipertensão arterial sistêmica), outras doenças sistêmicas, medicação em uso], realizado exame físico extra oral, com aferição da pressão arterial, exame físico intra-oral [para pesquisa de xerostomia, candidíase (pseudomembranosa, eritematosa, leucoplásica, queilite angular), GUNA úlcera aftosa recorrente, herpes simples, síndrome da boca ardente], índice CPOD, índice periodontal comunitário (ICP), índice gengival (IG), presença de cálculo, índice de placa, índice de maloclusão], exames complementares (avaliação do fluxo salivar, aferição da glicemia capilar e teste rápido de hemoglobina glicada) e o preenchimento do questionário Oral health impact profile (OHIP-14). Foram avaliados 26 pacientes, 11 do sexo masculino e 15 do sexo feminino, sendo que a média de idade do diagnóstico variou de 06 meses a 26 anos de idade, o tempo decorrente desde o diagnóstico variou de 1 a 37 anos, 61,53% dos pacientes apresentavam alguma microangiopatia e 27% dos pacientes alguma macroangiopatia. A manifestação bucal mais encontrada foi a xerostomia (61,53%), seguida da queilite angular (23,07%), a média do CPOD foi de 13,26, 50% dos pacientes apresentavam ICP escore 2 e os outros 50% apresentavam escore 3 e 4, 84,61% apresentavam gengivite moderada e a média do IP foi de 2,19. A maloclusão leve foi encontrada em 69% dos pacientes e 92,30% dos pacientes apresentavam fluxo salivar normal, 16 pacientes estavam com hiperglicemia, 23 pacientes apresentavam hemoglobina glicada descompensada e 58% dos pacientes apresentaram um impacto fraco de saúde bucal na qualidade de vida Concluímos que nossos pacientes com DM1 são jovens, com da glicemia e DM descompensados, apresentam a doença há mais de 10 anos, e desenvolveram microangiopatias e macroangiopatias como a doença renal e a hipertensão arterial. Apresentam poucas manifestações bucais, sendo a mais comum a xerostomia; e uma condição bucal satisfatória, em decorrência do acesso ao tratamento odontológico, independentemente da compensação da glicemia. / Diabetes mellitus type 1 is characterized by hyperglycemia due to the absence of insulin secretion caused by destruction of pancreatic beta cells, usually by autoimmune disease. The aim of this study was to establish the profile of the type 1 diabetic patients treated at CAPE FOUSP recognizing the systemic and oral complications of diabetes in these patients. We collected demographic data, medical history [age at diagnosis, history of ketoacidosis, hypoglycemic and hyperglycemic crisis, highest and lowest glycemia recorded, presence of microangiopathy (retinopathy, kidney disease, neuropathy) and macroangiopathy (cardiovascular disease, arterial hypertension), other systemic diseases, drugs in use], and performed blood pressure measurement, and extra and intra oral physical examination [searching for xerostomia, candidiasis (pseudomembranous, erythematous, leucoplakia, angular cheilitis), GUNA, aphthous ulcer, herpes simplex, burning mouth syndrome], DMFT index, community periodontal index (ICP), gingival index (GI), presence of calculus, plaque index, index of malocclusion], complementary tests (measurement of salivary flow and glycemia and a rapid test for glycated hemoglobin) and completing the questionnaire \" Oral health impact profile\" (OHIP - 14). We evaluated 26 patients, 11 males and 15 females, with age of diagnosis from 06 months to 26 years, time elapsed since diagnosis ranged from 1 to 37 years, 61.53 % presented with some microangiopathy and 27 % with macroangiopathy. The most frequent oral manifestation was xerostomia (61.53 %), followed by angular cheilitis (23.07%), the mean DMFT was 13.26, 50 % of patients had ICP score 2 and 50 % had score 3 and 4, 84.61% had moderate gingivitis and mean PI was 2.19. The slight malocclusion was found in 69 % of patients and 92.30 % of patients had normal salivary flow, 16 patients had hyperglycemia, 23 patients had glycated hemoglobin decompensated and 58 % of patients had a weak impact of oral health on quality of life. We conclude that our DM1 patients are young, with blood glucose and DM decompensated with diabetes for over 10 years, and developed microangiopathy and macroangiopathy like kidney disease and hypertension. Few patients have oral manifestations, and the most common is xerostomia, and a satisfactory oral health as a result of access to dental treatment, regardless of the rates of blood glucose.

Animal and human studies have consistently demonstrated that recurrent hypoglycaemia (RH) blunts both hormonal and behavioral counter regulatory responses (CRR) to further episodes of hypoglycaemia. It is now well established that the brain is involved in regulating whole-body glucose homeostasis, including the CRR to hypoglycaemia. The aim of the current study was to investigate if adaptations occur, following RH, which are intrinsic to glucose-sensing neurons in the absence of synaptic/glial inputs or signals from the periphery. Utilising the GT1-7 hypothalamic mouse cell line as an in vitro model of homogenous glucose-excited neurons, the current study has demonstrated that recurrent low glucose exposure reprograms intracellular metabolism towards a “hypometabolic state”. This result occurs in conjunction with an attenuated ability of the cells to hyperpolarise in response to low glucose and a reduction in the sensitivity of the KATP channel to activation by MgADP. In an attempt to reverse the changes observed in KATP channel activity, the SUR1-selective KATP channel opener, NN414, was applied chronically to GT1-7 cells. However, chronic KATP channel activation severely reduced channel conductance and sensitivity to activation by MgADP and further NN414 application. These results suggest that chronic activation of the KATP channel leads to the induction of a negative feedback mechanism to reduce channel activity. This may be in an attempt to maintain neuronal membrane potential within a physiological range. These results also suggest activation of central KATP channels during RH may be driving the resulting defective CRR. However, adaptations in metabolism following RH may also be altering the function of central KATP channels.

Forskning visar att ungdomar med typ 1 diabetes (T1D) har dubbelt så stor risk att drabbas av en ätstörning jämfört med ungdomar utan T1D. Dessutom ökar även mortalitet och morbiditet avsevärt hos ungdomarna med denna kombination. Syftet med litteraturstudien var att beskriva vad ungdomars upplevelser är i samband med ätstörningar och T1D. Dataanalysen genomfördes med inspiration från metoden innehållsanalys. Litteraturstudiens resultat visar kunskap från sju vetenskapliga artiklar. Efter tolkningen av resultaten i de vetenskapliga artiklarna formulerades fem teman: Social dimension, Fysisk dimension, Emotionell dimension, Triggerfaktorer och Coping. Resultatet gestaltade att stöd från familj och vänner upplevdes underlättande för ungdomarna, men även som ett ofullständigt stöd. Stödet från sjukvårdspersonalen upplevdes betydelsefullt. En del av ungdomarna upplevde negativa kroppsbilder, vilket föranledde till underdosering av insulin. Ätstörningarna kunde förorsaka depressiva känslor och samtidigt upplevd kroppskontroll. Stressade livssituationer kunde trigga igång ätstörningen. Upplevda copingstrategier som gav stöd i återhämtningen från ätstörningen var att dela sina erfarenheter med ungdomar i samma situation. Litteraturstudien visar att sjuksköterskan kan vara stödjande för ungdomar med T1D och ätstörningar genom att visa ett förhållningssätt i former av att vara lyssnande, icke dömande och visa tilltro. Litteraturstudien visar behov av ytterligare forskning för ett mer evidensbaserat kliniskt vårdande. / Research shows that adolescents with T1D runs a double risk of eating disorders compared to adolescents without T1D. Additionally, morbidity and mortality increases considerably at the combination. The aim of this literature study was to describe adolescents' experiences of living with T1D and eating disorders. The results in this literature study shows knowledge from seven scientific articles. Data analysis was inspired by content analysis. The results in this literature study shows knowledge from seven scientific articles. The interpretation resulted in five formulated themes: Social dimension, Physical dimension, Emotional dimension, Triggers and Coping. Results indicate that support originating from family, friends and healthcare professionals was experienced as facilitating, but also as an uncomplete support. Some adolescents experienced negative body images, which conduced to insulin omission. The eating disorders provided depressive feelings and simultaneously experienced body control. Stressed life situations could trigger eating disorders. Coping strategies which aided the recovery of eating disorders was sharing experiences with peers. This literature study indicate that nurses can be supportive for adolescents with T1D and eating disorders through approaching in forms of being listening, non-judging and trustful. This literature study display requirements of supplementary research for a more evidence based clinical caring.

Aims: Thiazolidinediones have been advocated as second or third line insulin sensitizing agents in the management of type 2 diabetes (T2DM). Their widespread use has been hampered by concerns about their cardiovascular safety, including fluid retention. Metformin is established as first-line glucose-lowering pharmacotherapy in T2DM. It has also been suggested that it may have benefits in alleviating insulin resistance in type 1 diabetes (T1DM). This thesis examined: (i) cardiovascular, renal and metabolic differences between individuals with T2DM ‘tolerant’ or ‘intolerant’ of TZDs; (ii) risk factors for TZD-associated oedema in T2DM; and (iii) the potential for metformin as adjunct therapy in T1DM. Methods: (i) A small clinical study characterising TZD tolerant and intolerant individuals with T2DM; (ii) A population-based epidemiological study of TZD induced oedema in individuals with T2DM in Tayside, Scotland (using incident loop diuretic prescription as a surrogate); (iii) A systematic review and meta-analysis of published studies of adjunct metformin in T1DM. Results (i) During a five-day high sodium diet, two known TZD-intolerant individuals with T2DM had reductions in haematocrit, aldosterone, and diastolic BP and increases in ANP and central and peripheral augmentation indices which were outwith reference ranges derived from nine TZD-tolerant individuals; (ii) Predictors of time to loop diuretic prescription included age, body mass index, systolic BP, haematocrit, ALT and macrovascular disease but rates of this outcome did not differ by therapy: 4.3% (TZDs) vs 4.7% (other agents) [unadjusted OR 0.909 (95% CI 0.690, 1.196); p = 0.493]; (iii) In meta-analysis of nine small studies in T1DM (192.8 patient-years of follow-up), metformin was associated with a reduction in total daily insulin dose (6.6 units/day; p < 0.001) but no studies examined cardiovascular surrogates or outcomes. Conclusions: Hypotheses were generated for several potential biomarkers predictive of TZD-induced oedema but the clinical importance of TZDs as a risk factor for oedema in individuals with T2DM was questioned. As there is some evidence for the safety of metformin as an adjunct therapy in T1DM but little evidence of efficacy, larger studies are warranted.