RESUMO
Birth by Cesarean section increases the risk of developing type 1 diabetes later in life. We aimed to elucidate common regulatory processes observed after Cesarean section and the development of islet autoimmunity, which precedes type 1 diabetes, by investigating the transcriptome of blood cells in the developing immune system. To investigate Cesarean section effects, we analyzed longitudinal gene expression profiles from peripheral blood mononuclear cells taken at several time points from children with increased familial and genetic risk for type 1 diabetes. For islet autoimmunity, we compared gene expression differences between children after initiation of islet autoimmunity and age-matched children who did not develop islet autoantibodies. Finally, we compared both results to identify common regulatory patterns. We identified the pentose phosphate pathway and pyrimidine metabolism - both involved in nucleotide synthesis and cell proliferation - to be differentially expressed in children born by Cesarean section and after islet autoimmunity. Comparison of global gene expression signatures showed that transcriptomic changes were systematically and significantly correlated between Cesarean section and islet autoimmunity. Moreover, signatures of both Cesarean section and islet autoimmunity correlated with transcriptional changes observed during activation of isolated CD4+ T lymphocytes. In conclusion, we identified shared molecular changes relating to immune cell activation in children born by Cesarean section and children who developed autoimmunity. Our results serve as a starting point for further investigations on how a type 1 diabetes risk factor impacts the young immune system at a molecular level.
Assuntos
Autoimunidade/genética , Cesárea/efeitos adversos , Regulação da Expressão Gênica , Ilhotas Pancreáticas/imunologia , Autoanticorpos/sangue , Linfócitos T CD4-Positivos , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/imunologia , Feminino , Humanos , Lactente , Leucócitos Mononucleares/fisiologia , Fatores de RiscoRESUMO
AIMS: Children and adolescents with a family history of diabetes are at increased risk of overweight, but little is known about the potentially beneficial effects of physical activity on these children. The objective of this study was to investigate the association between moderate to vigorous physical activity (MVPA) and metabolic and inflammatory risks in children and adolescents with a family background of Type 1 diabetes or gestational diabetes. METHODS: Valid MVPA measurements, made with accelerometers, were available from 234 participants (median age, 10.2 years) who had a first-degree relative with either Type 1 or gestational diabetes. Anthropometric and metabolic measurements were made and cytokines measured, and were correlated with MVPA measurements, with stepwise adjustment for confounding factors, in a cross-sectional analysis. RESULTS: MVPA was negatively associated with insulin and C-peptide during challenge with an oral glucose tolerance test. MVPA was also significantly positively associated with the insulin sensitivity index, whereas no consistently significant associations were found between MVPA and BMI, blood pressure or cytokine levels. DISCUSSION: Our findings indicate that physical activity may have beneficial effects on insulin and C-peptide metabolism in children and adolescents with a family background of diabetes, but show no evidence of a protective association with other health-related outcomes.
Assuntos
Peptídeo C/sangue , Diabetes Mellitus Tipo 1 , Diabetes Gestacional , Exercício Físico/fisiologia , Glucose/farmacologia , Insulina/sangue , Anamnese , Adolescente , Criança , Estudos de Coortes , Estudos Transversais , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Gestacional/epidemiologia , Feminino , Alemanha/epidemiologia , Teste de Tolerância a Glucose , Humanos , Masculino , Anamnese/estatística & dados numéricos , Gravidez , Fatores de RiscoRESUMO
OBJECTIVE: Type 1 diabetes can be identified by the presence of beta-cell autoantibodies that often arise in the first few years of life. The purpose of this perspective is to present the case for primary prevention of beta-cell autoimmunity and to provide a study design for its implementation in Europe. METHODS: We examined and summarized recruitment strategies, enrollment rates, and outcomes in published TRIGR, FINDIA and BABYDIET primary prevention trials, and the TEDDY intensive observational study. A proposal for a recruitment and implementation strategy to perform a phase II/III primary prevention randomized controlled trial in infants with genetic risk for developing beta-cell autoimmunity is outlined. RESULTS: Infants with a family history of type 1 diabetes (TRIGR, BABYDIET, TEDDY) and infants younger than age 3 months from the general population (FINDIA, TEDDY) were enrolled into these studies. All studies used HLA genotyping as part of their eligibility criteria. Predicted beta-cell autoimmunity risk in the eligible infants ranged from 3% (FINDIA, TEDDY general population) up to 12% (TRIGR, BABYDIET). Amongst eligible infants, participation was between 38% (TEDDY general population) and 97% (FINDIA). Outcomes, defined as multiple beta-cell autoantibodies, were consistent with predicted risks. We subsequently modeled recruitment into a randomized controlled trial (RCT) that could assess the efficacy of oral insulin treatment as adapted from the Pre-POINT pilot trial. The RCT would recruit infants with and without a first-degree family history of type 1 diabetes and be based on general population genetic risk testing. HLA genotyping and, for the general population, genotyping at additional type 1 diabetes susceptibility SNPs would be used to identify children with around 10% risk of beta-cell autoimmunity. The proposed RCT would have 80% power to detect a 50% reduction in multiple beta-cell autoantibodies by age 4 years at a two-tailed alpha of 0.05, and would randomize around 1160 infants to oral insulin or placebo arms in order to fulfill this. It is estimated that recruitment would require testing of between 400,000 and 500,000 newborns or infants. CONCLUSION: It is timely and feasible to establish a platform for primary prevention trials for type 1 diabetes in Europe. This multi-site European infrastructure would perform RCTs, supply data coordination and biorepository, provide cohorts for mechanistic and observational studies, and increase awareness for autoimmune diabetes.
RESUMO
The pregnancy outcomes in women with gestational diabetes mellitus (GDM) and 'overt diabetes in pregnancy' were compared and the need for further subclassification was investigated with respect to postpartum outcome risk. Data from 944 women who had been uniformly diagnosed as having GDM in Munich, Germany, between 1998 and 2010, were re-classified into GDM and 'overt diabetes in pregnancy'. Pregnancy related outcomes in the offspring were derived from Bavarian birth registry data. Classification and regression trees were used to identify further GDM sub-phenotypes. In total, 88 women (9.3%) were re-classified as having 'overt diabetes in pregnancy'. Compared to women with GDM, women with 'overt diabetes in pregnancy' used insulin more frequently, and were at increased risk for large for gestational age infants [odds ratio 2.50 (95% confidence interval 1.02, 6.13)], preterm delivery [odds ratio 3.28 (1.02, 10.50)], and low APGAR-score at 5 min [odds ratio 12.70 (1.58, 102.2)]. In the 856 women with GDM, classification and regression tree analyses provided further risk stratification in that a combination of fasting glucose>5.3 mmol/l and 1-h glucose>11.1 mmol/l at GDM diagnosis predicted insulin requirement [OR 5.57 (3.75, 8.27) compared to the rest], and maternal body mass index (BMI)≥35 kg/m(2) predicted large for gestational age status. The new differentiation between GDM and 'overt diabetes in pregnancy' is a first step towards refining classification relevant to fetal and maternal postpartum risk. A combination of glucose levels and maternal BMI at diagnosis of GDM may provide further improvement.
Assuntos
Diabetes Gestacional/epidemiologia , Medição de Risco , Organização Mundial da Saúde , Adulto , Intervalos de Confiança , Feminino , Humanos , Razão de Chances , Gravidez , Resultado da Gravidez , Prevalência , Análise de RegressãoRESUMO
AIMS: Women with gestational diabetes mellitus (GDM) have an increased risk of diabetes postpartum. We developed a score to predict the long-term risk of postpartum diabetes using clinical and anamnestic variables recorded during or shortly after delivery. METHODS: Data from 257 GDM women who were prospectively followed for diabetes outcome over 20 years of follow-up were used to develop and validate the risk score. Participants were divided into training and test sets. The risk score was calculated using Lasso Cox regression and divided into four risk categories, and its prediction performance was assessed in the test set. RESULTS: Postpartum diabetes developed in 110 women. The computed training set risk score of 5 × body mass index in early pregnancy (per kg/m(2)) + 132 if GDM was treated with insulin (otherwise 0) + 44 if the woman had a family history of diabetes (otherwise 0) - 35 if the woman lactated (otherwise 0) had R (2) values of 0.23, 0.25, and 0.33 at 5, 10, and 15 years postpartum, respectively, and a C-Index of 0.75. Application of the risk score in the test set resulted in observed risk of postpartum diabetes at 5 years of 11 % for low risk scores ≤140, 29 % for scores 141-220, 64 % for scores 221-300, and 80 % for scores >300. CONCLUSIONS: The derived risk score is easy to calculate, allows accurate prediction of GDM-related postpartum diabetes, and may thus be a useful prediction tool for clinicians and general practitioners.
Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Gestacional/epidemiologia , Adulto , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Gestacional/diagnóstico , Feminino , Humanos , Período Pós-Parto , Gravidez , Medição de Risco/métodos , Fatores de RiscoRESUMO
Children born by Caesarean Section have a higher risk for type 1 diabetes. We aimed to investigate whether Caesarean Section leads to alterations of the immune response in children with familial risk for type 1 diabetes. We examined measures of innate and adaptive immune responses in 94 prospectively followed children, including 40 born by Caesarean Section. Proinflammatory serum cytokine concentrations were determined at age 6 months. As a measure of vaccine response, IgG1, IgG2, and IgG4 tetanus antibody titers and CD4(+) T cell proliferation against tetanus toxoid were quantified. Compared to infants born by vaginal delivery, infants born by Caesarean Section had lower concentrations of the cytokines IFN-É£ (p=0.014) and IL-8 (p=0.005), and weaker CD4(+) T cell responses to tetanus measured in the first (p=0.007) and second year (p=0.047) of life. Overall, our findings provide evidence that the mode of delivery influences the immune status and responsiveness during childhood.
Assuntos
Imunidade Adaptativa/imunologia , Cesárea , Diabetes Mellitus Tipo 1/imunologia , Interferon gama/imunologia , Interleucina-8/imunologia , Toxoide Tetânico/imunologia , Anticorpos Antibacterianos/imunologia , Linfócitos T CD4-Positivos , Estudos de Casos e Controles , Parto Obstétrico , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/genética , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Imunoglobulina G , Lactente , Interleucina-10/imunologia , Interleucina-12/imunologia , Interleucina-1beta/imunologia , Interleucina-2/imunologia , Interleucina-6/imunologia , Masculino , Estudos Prospectivos , Toxina Tetânica/imunologia , Fator de Necrose Tumoral alfa/imunologiaAssuntos
Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/genética , Diagnóstico Precoce , Predisposição Genética para Doença/genética , Fenótipo , Administração Intranasal , Administração Oral , Adolescente , Autoanticorpos/sangue , Criança , Diabetes Mellitus Tipo 1/classificação , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/imunologia , Progressão da Doença , Interação Gene-Ambiente , Genótipo , Humanos , Insulina/administração & dosagem , Células Secretoras de Insulina/imunologia , Prognóstico , Fatores de RiscoRESUMO
OBJECTIVES: Body size is postulated to modulate type 1 diabetes as either a trigger of islet autoimmunity or an accelerator to clinical onset after seroconversion. As overweight and obesity continue to rise among children, the aim of this study was to determine whether human leukocyte antigen DQ (HLA-DQ) genotypes may be related to body size among children genetically at risk for type 1 diabetes. METHODS: Repeated measures of weight and height were collected from 5969 children 2-4 years of age enrolled in The Environmental Determinants of Diabetes in the Young prospective study. Overweight and obesity was determined by the International Obesity Task Force cutoff values that correspond to body mass index (BMI) of 25 and 30 kg m(-)(2) at age 18. RESULTS: The average BMI was comparable across specific HLA genotypes at every age point. The proportion of overweight was not different by HL A, but percent obesity varied by age with a decreasing trend among DQ2/8 carriers (P for trend=0.0315). A multivariable regression model suggested DQ2/2 was associated with higher obesity risk at age 4 (odds ratio, 2.41; 95% confidence interval, 1.21-4.80) after adjusting for the development of islet autoantibody and/or type 1 diabetes. CONCLUSIONS: The HLA-DQ2/2 genotype may predispose to obesity among 2-4-year-old children with genetic risk for type 1 diabetes.
Assuntos
Autoanticorpos/genética , Autoimunidade/genética , Diabetes Mellitus Tipo 1/genética , Antígenos HLA-DQ/genética , Obesidade Infantil/genética , Idade de Início , Peso ao Nascer , Estatura , Índice de Massa Corporal , Peso Corporal , Pré-Escolar , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/imunologia , Feminino , Finlândia/epidemiologia , Predisposição Genética para Doença , Genótipo , Alemanha/epidemiologia , Humanos , Ilhotas Pancreáticas , Masculino , Programas de Rastreamento , Mães , Obesidade Infantil/epidemiologia , Obesidade Infantil/imunologia , Prevalência , Estudos Prospectivos , Fatores de Risco , Suécia/epidemiologia , Estados Unidos/epidemiologiaRESUMO
Autoimmune diabetes is characterized by autoantigen-specific T cell-mediated destruction of pancreatic islet beta cells, and CD8(+) T cells are key players during this process. We assessed whether the bitransgenic RIP-CD80 x RIP-LCMV-GP (RIP-CD80GP) mice may be a versatile antigen-specific model of inducible CD8(+) T cell-mediated autoimmune diabetes. Antigen-encoding DNA, peptide-loaded dendritic cells and antigen plus incomplete Freund's adjuvant were used for vaccination. Of 14 pancreatic proteins tested by DNA vaccination, murine pre-proinsulin 2 (100% of mice; median time after vaccination, 60 days) and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) (77%, 58 days) could induce diabetes. Vaccination with DNA encoding for zinc transporter 8, Ia-2, Ia-2ß, glutamic acid decarboxylase 67 (Gad67), chromogranin A, insulinoma amyloid polypeptide and homeobox protein Nkx-2.2 induced diabetes development in 25-33% of mice. Vaccination with DNA encoding for Gad65, secretogranin 5, pancreas/duodenum homeobox protein 1 (Pdx1), carboxyl ester lipase, glucagon and control hepatitis B surface antigen (HBsAg) induced diabetes in <20% of mice. Diabetes induction efficiency could be increased by DNA vaccination with a vector encoding a ubiquitin-antigen fusion construct. Diabetic mice had florid T cell islet infiltration. CD8(+) T cell targets of IGRP were identified with a peptide library-based enzyme-linked immunospot assay, and diabetes could also be induced by vaccination with major histocompatibility complex (MHC) class I-restricted IGRP peptides loaded on mature dendritic cells. Vaccination with antigen plus incomplete Freund's adjuvant, which can prevent diabetes in other models, led to rapid diabetes development in the RIP-CD80GP mouse. We conclude that RIP-CD80GP mice are a versatile model of antigen specific autoimmune diabetes and may complement existing mouse models of autoimmune diabetes for evaluating CD8(+) T cell-targeted prevention strategies.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Glucose-6-Fosfatase/imunologia , Insulina/imunologia , Precursores de Proteínas/imunologia , Vacinação/métodos , Animais , Antígeno B7-1/genética , Antígeno B7-1/imunologia , Linfócitos T CD8-Positivos/metabolismo , DNA/genética , DNA/imunologia , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/genética , Adjuvante de Freund/imunologia , Glucose-6-Fosfatase/genética , Glicoproteínas/genética , Glicoproteínas/imunologia , Insulina/genética , Ilhotas Pancreáticas/imunologia , Estimativa de Kaplan-Meier , Lipídeos/imunologia , Vírus da Coriomeningite Linfocítica/genética , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Regiões Promotoras Genéticas/genética , Regiões Promotoras Genéticas/imunologia , Precursores de Proteínas/genética , Ratos , Fatores de Tempo , Vacinação/efeitos adversos , Vacinas de DNA/imunologia , Proteínas Virais/genética , Proteínas Virais/imunologiaRESUMO
AIMS/HYPOTHESIS: Viruses are candidate causative agents in the pathogenesis of autoimmune (type 1) diabetes. We hypothesised that children with a rapid onset of type 1 diabetes may have been exposed to such agents shortly before the initiation of islet autoimmunity, possibly at high dose, and thus study of these children could help identify viruses involved in the development of autoimmune diabetes. METHODS: We used next-generation sequencing to search for viruses in plasma samples and examined the history of infection and fever in children enrolled in The Environmental Determinants of Diabetes in the Young (TEDDY) study who progressed to type 1 diabetes within 6 months from the appearance of islet autoimmunity, and in matched islet-autoantibody-negative controls. RESULTS: Viruses were not detected more frequently in plasma from rapid-onset patients than in controls during the period surrounding seroconversion. In addition, infection histories were found to be similar between children with rapid-onset diabetes and control children, although episodes of fever were reported less frequently in children with rapid-onset diabetes. CONCLUSIONS/INTERPRETATION: These findings do not support the presence of viraemia around the time of seroconversion in young children with rapid-onset type 1 diabetes.
Assuntos
Diabetes Mellitus Tipo 1/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Vírus/genética , Autoimunidade/genética , Autoimunidade/imunologia , Pré-Escolar , Diabetes Mellitus Tipo 1/virologia , Feminino , Humanos , Lactente , Recém-Nascido , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/metabolismo , Masculino , Viroses/genéticaRESUMO
AIMS/HYPOTHESIS: Islet autoantibody-positive children progress to type 1 diabetes at variable rates. In our study, we asked whether characteristic autoantibody and/or gene profiles could be defined for phenotypes showing extreme progression. METHODS: Autoantibodies to insulin (IAA), GAD (GADA), insulinoma-associated antigen-2 (IA-2A) and zinc transporter 8 (ZnT8A) were measured in follow-up sera, and genotyping for type 1 diabetes susceptibility genes (HLA-DR/HLA-DQ, INS variable number of tandem repeats [VNTR] and single nucleotide polymorphisms at PTPN22, PTPN2, ERBB3, IL2, SH2B3, CTLA4, IFIH1, KIAA0350 [also known as CLEC16A], CD25, IL18RAP, IL10, COBL) was performed on the DNA samples of children born to a parent with type 1 diabetes and prospectively followed from birth for up to 22 years. RESULTS: Of the 1,650 children followed, 23 developed multiple autoantibodies and progressed to diabetes within 3 years (rapid progressors), while 24 children developed multiple autoantibodies and remained non-diabetic for more than 10 years from seroconversion (slow progressors). Rapid and slow progressors were similar with respect to HLA-DR/HLA-DQ genotypes, development of IAA, GADA and ZnT8A, and progression to multiple autoantibodies. In contrast, IA-2A development was considerably delayed in the slow progressors. Furthermore, both groups were effectively distinguished by the combined presence or absence of type 1 diabetes susceptibility alleles of non-HLA genes, most notably IL2, CD25, INS VNTR, IL18RAP, IL10, IFIH1 and PTPN22, and discrimination was improved among children carrying high-risk HLA-DR/HLA-DQ genotypes. CONCLUSIONS/INTERPRETATION: Our data suggest that genotypes of non-HLA type 1 diabetes susceptibility genes influence the likelihood or rate of diabetes progression among children with multiple islet autoantibodies.
Assuntos
Autoanticorpos/imunologia , Proteínas de Transporte de Cátions/imunologia , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Insulina/imunologia , Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/imunologia , Proteínas Adaptadoras de Transdução de Sinal , Adolescente , Antígeno CTLA-4/genética , Criança , Pré-Escolar , RNA Helicases DEAD-box/genética , Feminino , Predisposição Genética para Doença/genética , Genótipo , Antígenos HLA-DQ/genética , Humanos , Lactente , Recém-Nascido , Helicase IFIH1 Induzida por Interferon , Interleucina-10/genética , Subunidade beta de Receptor de Interleucina-18/genética , Subunidade alfa de Receptor de Interleucina-2/genética , Peptídeos e Proteínas de Sinalização Intracelular , Lectinas Tipo C/genética , Masculino , Proteínas dos Microfilamentos/genética , Proteínas de Transporte de Monossacarídeos/genética , Polimorfismo de Nucleotídeo Único/genética , Proteína Tirosina Fosfatase não Receptora Tipo 2/genética , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Proteínas/genética , Receptor ErbB-3/genética , Transportador 8 de ZincoRESUMO
Very little is known about the role of the innate immune system in the course of human type 1 diabetes. Here we investigated neutrophil numbers along with other leukocyte populations in patients at diagnosis of type 1 diabetes and during prediabetes. Complete and differential blood counts were analyzed from 107 adult patients with newly diagnosed type 1 diabetes, 21 children with persistent islet autoantibodies and a family history of type 1 diabetes, and 1 238 age and gender matched control subjects, all individuals without any signs of acute infection.Adult patients with newly diagnosed type 1 diabetes had significantly lower total WBC (p<1×10â»6), neutrophil (p<1×10â»6), basophil (p<1×10â»6), monocyte (p=4×10â»6) and lymphocyte (p<1×10â»6) counts compared to control subjects. Erythrocyte, eosinophil and platelet counts did not differ between groups. Similarly, children with persistent islet autoantibodies had decreased WBC (p=0.001), neutrophils (p=0.003), and lymphocytes (p=0.006) in comparison to control children. Our findings demonstrate a perturbation of leukocyte homeostasis at and prior to onset of type 1 diabetes suggesting a general involvement of the innate immune system in the pathogenesis of type 1 diabetes.
Assuntos
Diabetes Mellitus Tipo 1/sangue , Leucócitos/citologia , Neutrófilos/citologia , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/imunologia , Feminino , Humanos , Contagem de Leucócitos , Leucócitos/imunologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Adulto JovemRESUMO
Genome-wide association studies have identified gene regions associated with type 1 diabetes. The aim of this study was to determine how the combined allele frequency of multiple susceptibility genes can stratify islet autoimmunity and/or type 1 diabetes risk. Children of parents with type 1 diabetes and prospectively followed from birth for the development of islet autoantibodies and diabetes were genotyped for single-nucleotide polymorphisms at 12 type 1 diabetes susceptibility genes (ERBB3, PTPN2, IFIH1, PTPN22, KIAA0350, CD25, CTLA4, SH2B3, IL2, IL18RAP, IL10 and COBL). Non-human leukocyte antigen (HLA) risk score was defined by the total number of risk alleles at these genes. Receiver operator curve analysis showed that the non-HLA gene combinations were highly effective in discriminating diabetes and most effective in children with a high-risk HLA genotype. The greatest diabetes discrimination was obtained by the sum of risk alleles for eight genes (IFIH1, CTLA4, PTPN22, IL18RAP, SH2B3, KIAA0350, COBL and ERBB3) in the HLA-risk children. Non-HLA-risk allele scores stratified risk for developing islet autoantibodies and diabetes, and progression from islet autoimmunity to diabetes. Genotyping at multiple susceptibility loci in children from affected families can identify neonates with sufficient genetic risk of type 1 diabetes to be considered for early intervention.
Assuntos
Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença , Adolescente , Criança , Pré-Escolar , Frequência do Gene , Loci Gênicos , Antígenos HLA/genética , Humanos , Lactente , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Adulto JovemRESUMO
The impact of gestation and fetal-maternal interactions on pre-existent autoimmune beta cell destruction is widely unknown. The aim of this study was to investigate the influence of gestation per se and fetal mismatching on the onset of autoimmune diabetes in female non-obese diabetic (NOD) mice. We examined cumulative diabetes frequencies of NOD dams mated to syngeneic NOD, haploidentical CByB6F1/J and fully mismatched C57BL/6J male mice. Pregnancy from NOD males neither increased nor accelerated the diabetes onset of NOD dams (71% by age 28 weeks) compared to unmated female NOD mice (81% by age 28 weeks; P = 0·38). In contrast, delayed diabetes onset was observed when NOD dams were mated at 10 weeks of age with major histocompatibility complex (MHC) haploidentical CByB6F1/J male mice (38% at age 28 weeks; P = 0·01). Mating with fully MHC mismatched C57BL/6J male mice (72% diabetes by age 28 weeks; P = 0·22) or mating with the haploidentical males at the later time-point of age 13 weeks (64% versus 91% in unmated litter-matched controls; P = 0·13) did not delay diabetes significantly in NOD females. Because infusion of haploidentical male mouse splenocytes was found previously to prevent diabetes in NOD mice we looked for, but found no evidence of, persistent chimeric lymphocytes from haploidentical paternal origin within the dams' splenocytes. Gestation per se appears to have no aggravating or ameliorating effects on pre-existent autoimmune beta cell destruction, but pregnancy from MHC partially mismatched males delays diabetes onset in female NOD mice.
Assuntos
Diabetes Mellitus Tipo 1/imunologia , Histocompatibilidade , Células Secretoras de Insulina/patologia , Animais , Diabetes Mellitus Tipo 1/patologia , Modelos Animais de Doenças , Feminino , Histocompatibilidade/imunologia , Humanos , Imunidade Materno-Adquirida , Isoantígenos/imunologia , Masculino , Troca Materno-Fetal , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , GravidezRESUMO
AIMS/HYPOTHESIS: Autoantibodies to zinc transporter 8 (ZnT8A) are associated with risk of type 1 diabetes. Apart from the SLC30A8 gene itself, little is known about the genetic basis of ZnT8A. We hypothesise that other loci in addition to SLC30A8 are associated with ZnT8A. METHODS: The levels of ZnT8A were measured in 2,239 British type 1 diabetic individuals diagnosed before age 17 years, with a median duration of diabetes of 4 years. Cases were tested at over 775,000 loci genome wide (including 53 type 1 diabetes associated regions) for association with positivity for ZnT8A. ZnT8A were also measured in an independent dataset of 855 family members with type 1 diabetes. RESULTS: Only FCRL3 on chromosome 1q23.1 and the HLA class I region were associated with positivity for ZnT8A. rs7522061T>C was the most associated single nucleotide polymorphism (SNP) in the FCRL3 region (p = 1.13 × 10(-16)). The association was confirmed in the family dataset (p ≤ 9.20 × 10(-4)). rs9258750A>G was the most associated variant in the HLA region (p = 2.06 × 10(-9) and p = 0.0014 in family cases). The presence of ZnT8A was not associated with HLA-DRB1, HLA-DQB1, HLA-A, HLA-B or HLA-C (p > 0.05). Unexpectedly, the two loci associated with the presence of ZnT8A did not alter risk of having type 1 diabetes, and the 53 type 1 diabetes risk loci did not influence positivity for ZnT8A, despite them being disease specific. CONCLUSIONS/INTERPRETATION: ZnT8A are not primary pathogenic factors in type 1 diabetes. Nevertheless, ZnT8A testing in combination with other autoantibodies facilitates disease prediction, despite the biomarker not being under the same genetic control as the disease.
Assuntos
Autoanticorpos/genética , Proteínas de Transporte de Cátions/genética , Diabetes Mellitus Tipo 1/genética , Anticorpos Anti-Insulina/genética , Polimorfismo de Nucleotídeo Único , Proteínas de Transporte de Cátions/imunologia , Criança , Diabetes Mellitus Tipo 1/imunologia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Anticorpos Anti-Insulina/imunologia , Masculino , Transportador 8 de ZincoRESUMO
AIMS/HYPOTHESIS: Seroconversion to islet autoantibodies precedes type 1 diabetes. This study aimed to identify periods of high seroconversion incidence, which could be targeted for mechanistic and therapeutic studies. METHODS: Incidence of islet autoantibodies was calculated in 1,650 genetically at-risk children followed with measurements of islet autoantibodies and thyroid autoantibodies at age 9 months and 2, 5, 8, 11, 14 and 17 years. Peak incidence periods were confirmed in a second cohort of 150 children followed until age 6 years with three-monthly samples up to age 3 years. RESULTS: Islet autoantibody incidence (per 1,000 person-years) was 18.5 until age 9 months, 21 from 9 months to 2 years and <10 for intervals after age 2 years. The second cohort confirmed peak incidence around age 9 months and demonstrated an absence of seroconversion before this age. Seroconversion to insulin autoantibodies occurred earlier than other autoantibodies (p<0.01 against glutamic acid decarboxylase [GAD]-, insulinoma-associated protein 2 [IA-2]- and zinc transporter 8 [ZnT8]-autoantibodies). Early peak seroconversion incidence was most evident in children with high-risk HLA DR3/4-DQ8 or DR4/4-DQ8 genotypes. CONCLUSION: The age period 9 months to 2 years is associated with a high incidence of activation of type 1 diabetes associated autoimmunity in genetically at-risk children and should be targeted for effective primary prevention strategies.
Assuntos
Autoanticorpos/sangue , Filho de Pais com Deficiência , Diabetes Mellitus Tipo 1/imunologia , Antígenos HLA-D/imunologia , Estado Pré-Diabético/imunologia , Adolescente , Idade de Início , Autoanticorpos/imunologia , Criança , Pré-Escolar , Estudos de Coortes , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/genética , Progressão da Doença , Feminino , Predisposição Genética para Doença , Genótipo , Alemanha/epidemiologia , Antígenos HLA-D/genética , Humanos , Incidência , Lactente , Estudos Longitudinais , Masculino , Reação em Cadeia da Polimerase , Estado Pré-Diabético/epidemiologia , Estado Pré-Diabético/genéticaRESUMO
AIMS/HYPOTHESIS: The aim of this study was to examine human enteroviruses (HEVs) and other intestinal viruses derived from children who participated in the Babydiet intervention study and to analyse the findings according to the appearance of islet autoantibodies, dietary intervention, maternal type 1 diabetes and clinical symptoms. METHODS: In the Babydiet study the influence of first gluten exposure (6 or 12 months) on the development of islet autoimmunity was investigated in 150 children with increased genetic and familial risk for type 1 diabetes. Blood and stool samples were collected at 3 monthly intervals until the age of 3 years and yearly thereafter. Infections and clinical symptoms were recorded daily for the first year. In the present study, 339 stool samples collected from 104 children during the first year of life were analysed for HEVs and a certain proportion of the samples were analysed for other intestinal viruses. RESULTS: HEV was detected in 32 (9.4%) samples from 24 (23.1%) children. Altogether 13 serotypes were identified, with HEV-A species being the most common. Children with gastrointestinal symptoms had norovirus (3/11) and sapovirus (1/11) infections in addition to HEV (1/11). Of the 104 children, 22 developed islet autoantibodies. HEV infections were detected in 18% (4/22) and 24% (20/82) of islet-autoantibody-positive and -negative children, respectively (p = 0.5). The prevalence of HEV was similar in the gluten-exposed groups and in children from mothers with type 1 diabetes or from affected fathers and/or siblings (p = 1.0 and 0.6, respectively). CONCLUSIONS/INTERPRETATION: No correlation was found between the presence of HEV in the first year of life and the development of islet autoantibodies. There was no association between HEV infections and dietary intervention, maternal diabetes or clinical symptoms.
Assuntos
Diabetes Mellitus Tipo 1/virologia , Infecções por Enterovirus/epidemiologia , Gravidez em Diabéticas/epidemiologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/imunologia , Enterovirus/imunologia , Enterovirus/isolamento & purificação , Infecções por Enterovirus/imunologia , Infecções por Enterovirus/virologia , Fezes/virologia , Feminino , Glutens/metabolismo , Humanos , Incidência , Lactente , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/virologia , Masculino , Gravidez , Prevalência , Fatores de RiscoRESUMO
Insulin autoantibodies (IAA) can appear in children within months of introducing solid foods to the diet and before clinical type 1 diabetes. The aim of this study was to determine whether infant dietary antigens could be immunizing agents of IAA. To this end, IAA binding to [(125) I]insulin was competed with food preparations and extracts of foods encountered in the infant diet (milk formulas, bovine milk, wheat flour, fowl meal). Bovine milk powder extracts inhibited IAA-positive samples from six of 53 children (age 0·3-14·0 years) participating in German prospective cohorts. Inhibition in these sera ranged from 23 to 100%. Competition was abolished when hydrolyzed milk powder was used. Competition with protein components of bovine milk found that two of the six milk-reactive sera were inhibited strongly by alpha- and beta-casein; none were inhibited by the milk proteins bovine serum albumin or lactoglobulins. The two casein-reactive sera had high affinity to alpha-casein (1·7×10(9) ; 3·1×10(9) l/mol), and lesser affinity to beta-casein (4·0×10(8) ; 7·0×10(7) l/mol) and insulin (2·6×10(8) ; 1·6×10(8) l/mol). No children with milk-reactive IAA developed autoantibodies to other islet autoantigens or diabetes (median follow-up 9·8 years). These results suggest that autoimmunity to insulin can occur infrequently via cross-reactivity to food proteins, but this form of IAA immunization does not appear to be associated with progression to diabetes.
Assuntos
Autoanticorpos/imunologia , Caseínas/imunologia , Anticorpos Anti-Insulina/imunologia , Insulina/imunologia , Adolescente , Animais , Autoanticorpos/metabolismo , Ligação Competitiva , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Caseínas/metabolismo , Caseínas/farmacologia , Bovinos , Proliferação de Células/efeitos dos fármacos , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Citometria de Fluxo , Humanos , Lactente , Alimentos Infantis , Insulina/metabolismo , Insulina/farmacologia , Anticorpos Anti-Insulina/metabolismo , Radioisótopos do Iodo , Proteínas do Leite/imunologia , Proteínas do Leite/metabolismo , Proteínas do Leite/farmacologia , Ligação Proteica , Soroalbumina BovinaRESUMO
The incidence of type 1 diabetes is increasing rapidly. Detecting the mechanisms underlying the autoimmune disease is a main goal of research. Studies investigating the pathogenesis of type 1 diabetes are working on the identification and characterization of exogenous, endogenous and genetic factors which induce or modify autoimmunity. Islet cell autoimmunity can be detected through screening for islet cell autoantibodies. This quantitative analysis allows the stratification of the individual risk for the development of type 1 diabetes. Prospective observational studies are most suitable to assess persons at risk, either because of the occurrence of type 1 diabetes in the family or because of a genotype associated with increased risk. Age-related factors which are analysed in observational studies include nutrition, increase in height and weight, childhood diseases and vaccinations as well as psychosocial aspects. Identification and characterization of these risk factors will serve as a basis for working on new approaches to prevent or to cure type 1 diabetes. Aim of this article is to provide an overview of the most relevant observational studies.