RESUMEN
The phenotype of autoreactive T cells in type 1 diabetes is described as Th1, Th17 and/or Th21, but is largely uncharacterized. We combined multi-parameter cytokine profiling and proliferation, and identified GM-CSF producing cells as a component of the response to beta cell autoantigens proinsulin and GAD65. Overall cytokine profiles of CD4+ T cell were not altered in type 1 diabetes. In contrast, patients with recent onset type 1 diabetes had increased frequencies of proinsulin-responsive CD4+CD45RA- T cells producing GM-CSF (p=0.002), IFNγ (p=0.004), IL-17A (p=0.008), IL-21 (p=0.011), and IL-22 (p=0.007), and GAD65-responsive CD4+CD45RA- T cells producing IL-21 (p=0.039). CD4+ T cells with a GM-CSF+IFNγ-IL-17A-IL-21-IL-22- phenotype were increased in patients for responses to both proinsulin (p=0.006) and GAD65 (p=0.037). GM-CSF producing T cells are a novel phenotype in the repertoire of T helper cells in type 1 diabetes and consolidate a Th1/Th17 pro-inflammatory pathogenesis in the disease.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Citocinas/inmunología , Diabetes Mellitus Tipo 1/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Autoantígenos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Células Cultivadas , Citocinas/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Expresión Génica/inmunología , Glutamato Descarboxilasa , Factor Estimulante de Colonias de Granulocitos y Macrófagos/biosíntesis , Humanos , Proinsulina/inmunología , Proinsulina/metabolismo , Células TH1/inmunología , Células TH1/metabolismo , Células Th17/inmunología , Células Th17/metabolismoRESUMEN
OBJECTIVE: In children with presymptomatic type 1 diabetes, intermittent hyperglycemia and rising hemoglobin A1c levels are a known signal of progression toward insulin-dependency. Episodes of hypoglycemia, however, have also been reported in one published case. We investigated the prevalence of hypoglycemia and its association with disease progression in children with presymptomatic type 1 diabetes. METHODS: We compared the frequency of hypoglycemic fasting blood glucose levels (<60 mg/dL) in 48 autoantibody negative and 167 multiple ß-cell autoantibody positive children aged 2 to 5 years. We classified the autoantibody positive children into three categories based on their glucose levels in fasting state (hypoglycemic [<60 mg/dL], normoglycemic [60-99 mg/dL] or hyperglycemic [≥100 mg/dL]). We then compared the glucose levels under challenge during oral glucose tolerance tests (OGTTs) between the three categories. RESULTS: In the autoantibody positive children, 5.1% of the fasting samples were hypoglycemic, while in the autoantibody negative children no hypoglycemia was observed. Hypoglycemia occurred more often in autoantibody positive children who had already entered stage 2 or stage 3 of type 1 diabetes than in stage 1 patients (P = 0.02). Children who had hypoglycemic compared to normoglycemic fasting blood glucose values had higher 120-minute blood glucose values under OGTT challenge, and a higher rate of pathological OGTTs (P = 0.04). CONCLUSIONS: Fasting hypoglycemia seems to be an indicator of disease progression in presymptomatic type 1 diabetes and may therefore represent a novel marker for the identification of children who should be monitored more closely for progression toward insulin-dependent type 1 diabetes.
Asunto(s)
Autoanticuerpos/sangre , Diabetes Mellitus Tipo 1/sangre , Hipoglucemia/etiología , Preescolar , Diabetes Mellitus Tipo 1/inmunología , Progresión de la Enfermedad , Femenino , Humanos , MasculinoRESUMEN
BACKGROUND: Although detection of children at high risk of developing type 1 diabetes and diagnosis of early stages is possible, up to now there exists no approved therapy to delay or prevent type 1 diabetes. Thus it is vital to develop evidence-based interventions. For this a sufficient number of trial participants is crucial but difficult to obtain especially in asymptomatic children. AIM: Identifying family characteristics that lead to or impede trial participation and analyze reasons stated by families for non-participation. METHODS: Participants for the Fr1da Insulin Intervention study are recruited from the Fr1da study, a population based screening for early stage type 1 diabetes in Bavaria. Families with eligible children were invited to enroll. We analyzed sex and age of the child, distance of the family to the study center in Munich and the existence of a first degree family member with type 1 as possible influential factors for study participation. We also analyzed reasons stated by families who declined study participation in a phone interview. RESULTS: Of 146 eligible children 77 (53%) were enrolled into the trial. None of the tested family characteristics differed significantly between the enrolling and the families not participating, but in general enrolling families lived closer to the study site than families not participating. This is also reflected in the reasons given by non-participating families. The most frequent reason stated were time restrictions. The second most frequent reason was the venous blood draw. CONCLUSION: The factors for non-participation identified in this project need be taken into account for the design of future trials in young children to ensure proper recruitment and thus to generate valid results for medical treatment of children. More research on the reason of participation and non-participation in clinical trials is needed.