Oral insulin immunotherapy in children at risk for type 1 diabetes in a randomised controlled trial

AIMS/HYPOTHESIS Oral administration of antigen can induce immunological tolerance. Insulin is a key autoantigen in childhood type 1 diabetes. Here, oral insulin was given as antigen-specific immunotherapy before the onset of autoimmunity in children from age 6~months to assess its safety and immune response actions on immunity and the gut microbiome. METHODS A phase I/II randomised controlled trial was performed in a single clinical study centre in Germany. Participants were 44 islet autoantibody-negative children aged 6~months to 2.99~years who had a first-degree relative with type 1 diabetes and a susceptible HLA DR4-DQ8-containing genotype. Children were randomised 1:1 to daily oral insulin (7.5~mg with dose escalation to 67.5~mg) or placebo for 12~months using a web-based computer system. The primary outcome was immune efficacy pre-specified as induction of antibody or T cell responses to insulin and measured in a central treatment-blinded laboratory. RESULTS Randomisation was performed in 44 children. One child in the placebo group was withdrawn after the first study visit and data from 22 insulin-treated and 21 placebo-treated children were analysed. Oral insulin was well tolerated with no changes in metabolic variables. Immune responses to insulin were observed in children who received both insulin (54.5%) and placebo (66.7%), and the trial did not demonstrate an effect on its primary outcome (p = 0.54). In exploratory analyses, there was preliminary evidence that the immune response and gut microbiome were modified by the INS genotype Among children with the type 1 diabetes-susceptible INS genotype (n = 22), antibody responses to insulin were more frequent in insulin-treated (72.7%) as compared with placebo-treated children (18.2%; p = 0.03). T cell responses to insulin were modified by treatment-independent inflammatory episodes. CONCLUSIONS/INTERPRETATION The study demonstrated that oral insulin immunotherapy in young genetically at-risk children was safe, but was not associated with an immune response as predefined in the trial primary outcome. Exploratory analyses suggested that antibody responses to oral insulin may occur in children with a susceptible INS genotype, and that inflammatory episodes may promote the activation of insulin-responsive T cells. TRIAL REGISTRATION Clinicaltrials.gov NCT02547519 FUNDING: The main funding source was the German Center for Diabetes Research (DZD e.V.)

Genetic scores to stratify risk of developing multiple islet autoantibodies and type 1 diabetes: A prospective study in children.

Around 0.3% of newborns will develop autoimmunity to pancreatic beta cells in childhood and subsequently develop type 1 diabetes before adulthood. Primary prevention of type 1 diabetes will require early intervention in genetically at-risk infants. The objective of this study was to determine to what extent genetic scores (two previous genetic scores and a merged genetic score) can improve the prediction of type 1 diabetes.This article is freely available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site

A public health antibody screening indicates a marked increase of SARS-CoV-2 exposure rate in children during the second wave.

Hippich et al update their surveillance of SARS-CoV-2 antibodies in the Bavarian childhood population and show an eight-fold prevalence increase during 2021 as compared to the end of first wave in 2020. Over 50% of positive children were asymptomatic

A classification and regression tree analysis identifies subgroups of childhood type 1 diabetes.

BACKGROUND: Diabetes in childhood and adolescence includes autoimmune and non-autoimmune forms with heterogeneity in clinical and biochemical presentations. An unresolved question is whether there are subtypes, endotypes, or theratypes within these forms of diabetes. METHODS: The multivariable classification and regression tree (CART) analysis method was used to identify subgroups of diabetes with differing residual C-peptide levels in patients with newly diagnosed diabetes before 20 years of age (n=1192). The robustness of the model was assessed in a confirmation and prognosis cohort (n=2722). FINDINGS: The analysis selected age, haemoglobin A1c (HbA1c), and body mass index (BMI) as split parameters that classified patients into seven islet autoantibody-positive and three autoantibody-negative groups. There were substantial differences in genetics, inflammatory markers, diabetes family history, lipids, 25-OH-Vitamin D3, insulin treatment, insulin sensitivity and insulin autoimmunity among the groups, and the method stratified patients with potentially different pathogeneses and prognoses. Interferon-ɣ and/or tumour necrosis factor inflammatory signatures were enriched in the youngest islet autoantibody-positive groups and in patients with the lowest C-peptide values, while higher BMI and type 2 diabetes characteristics were found in older patients. The prognostic relevance was demonstrated by persistent differences in HbA1c at 7 years median follow-up. INTERPRETATION: This multivariable analysis revealed subgroups of young patients with diabetes that have potential pathogenetic and therapeutic relevance. FUNDING: The work was supported by funds from the German Federal Ministry of Education and Research (01KX1818; FKZ 01GI0805; DZD e.V.), the Innovative Medicine Initiative 2 Joint Undertaking INNODIA (grant agreement No. 115797), the German Robert Koch Institute, and the German Diabetes Association

Physical activity is associated with lower insulin and C-peptide during glucose challenge in children and adolescents with family background of diabetes.

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

GM-CSF producing autoreactive CD4(+) T cells in type 1 diabetes.

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), IFN gamma (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+IFN gamma-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. (C) 2017 The Authors. Published by Elsevier Inc

Allele-specific methylation of type 1 diabetes susceptibility genes

The susceptibility to autoimmune diseases is influenced by genes encoding major histocompatibility complex (MHC) proteins. By examining the epigenetic methylation maps of cord blood samples, we found marked differences in the methylation status of CpG sites within the MHC genes (cis-metQTLs) between carriers of the type 1 diabetes risk haplotypes HLA-DRB1*03-DQA1*0501-DQB1*0201 (DR3-DQ2) and HLA-DRB1*04-DQA1*0301-DQB1*0302 (DR4-DQ8). These differences were found in children and adults, and were accompanied by reduced HLA-DR protein expression in immune cells with the HLA-DR3-DQ2 haplotype. Extensive cis-metQTLs were identified in all 45 immune and non-immune type 1 diabetes susceptibility genes analyzed in this study. We observed and validated a novel association between the methylation status of CpG sites within the LDHC gene and the development of insulin autoantibodies in early childhood in children who are carriers of the highest type 1 diabetes risk genotype. Functionally relevant epigenetic changes in susceptibility genes may represent therapeutic targets for type 1 diabetes

An age-related exponential decline in the risk of multiple islet autoantibody seroconversion during childhood.

OBJECTIVE: Islet autoimmunity develops before clinical type 1 diabetes and includes multiple and single autoantibody phenotypes. The objective was to determine age-related risks of islet autoantibodies that reflect etiology and improve screening for presymptomatic type 1 diabetes. RESEARCH DESIGN AND METHODS: The Environmental Determinants of Diabetes in the Young study prospectively monitored 8,556 genetically at-risk children at 3- to 6-month intervals from birth for the development of islet autoantibodies and type 1 diabetes. The age-related change in the risk of developing islet autoantibodies was determined using landmark and regression models. RESULTS: The 5-year risk of developing multiple islet autoantibodies was 4.3% (95% CI 3.8-4.7) at 7.5 months of age and declined to 1.1% (95% CI 0.8-1.3) at a landmark age of 6.25 years (P < 0.0001). Risk decline was slight or absent in single insulin and GAD autoantibody phenotypes. The influence of sex, HLA, and other susceptibility genes on risk subsided with increasing age and was abrogated by age 6 years. Highest sensitivity and positive predictive value of multiple islet autoantibody phenotypes for type 1 diabetes was achieved by autoantibody screening at 2 years and again at 5-7 years of age. CONCLUSIONS: The risk of developing islet autoimmunity declines exponentially with age, and the influence of major genetic factors on this risk is limited to the first few years of life

Progression from islet autoimmunity to clinical type 1 diabetes is influenced by genetic factors: Results from the prospective TEDDY study.

Background Progression time from islet autoimmunity to clinical type 1 diabetes is highly variable and the extent that genetic factors contribute is unknown.Methods In 341 islet autoantibody-positive children with the human leucocyte antigen (HLA) DR3/DR4-DQ8 or the HLA DR4-DQ8/DR4-DQ8 genotype from the prospective TEDDY (The Environmental Determinants of Diabetes in the Young) study, we investigated whether a genetic risk score that had previously been shown to predict islet autoimmunity is also associated with disease progression.Results Islet autoantibody-positive children with a genetic risk score in the lowest quartile had a slower progression from single to multiple autoantibodies (p=0.018), from single autoantibodies to diabetes (p=0.004), and by trend from multiple islet autoantibodies to diabetes (p=0.06). In a Cox proportional hazards analysis, faster progression was associated with an increased genetic risk score independently of HLA genotype (HR for progression from multiple autoantibodies to type 1 diabetes, 1.27, 95% CI 1.02 to 1.58 per unit increase), an earlier age of islet autoantibody development (HR, 0.68, 95% CI 0.58 to 0.81 per year increase in age) and female sex (HR, 1.94, 95% CI 1.28 to 2.93).Conclusions Genetic risk scores may be used to identify islet autoantibody-positive children with high-risk HLA genotypes who have a slow rate of progression to subsequent stages of autoimmunity and type 1 diabetes