Type 1 Diabetes Genetic Risk Contributes to Phenotypic Presentation in Monogenic Autoimmune Diabetes.

There is variability in early-onset autoimmune diabetes presentation in individuals with monogenic autoimmunity; the mechanism(s) underlying this is unclear. We examined whether type 1 diabetes (T1D) polygenic risk contributes to clinical phenotype in monogenic autoimmune diabetes. Individuals with monogenic autoimmune diabetes had higher T1D genetic risk scores compared with control cohorts, driven largely by increased presence of T1D-risk DR3-DQ2 haplotype.

Looking back at the TEDDY study: lessons and future directions.

The goal of the TEDDY (The Environmental Determinants of Diabetes in the Young) study is to elucidate factors leading to the initiation of islet autoimmunity (first primary outcome) and those related to progression to type 1 diabetes mellitus (T1DM; second primary outcome). This Review outlines the key findings so far, particularly related to the first primary outcome. The background, history and organization of the study are discussed.

Risk of celiac disease autoimmunity is modified by interactions between CD247 and environmental exposures.

Season of birth, viral infections, HLA haplogenotypes and non-HLA variants are implicated in the development of celiac disease and celiac disease autoimmunity, suggesting a combined role of genes and environmental exposures. The aim of the study was to further decipher the biological pathways conveying the season of birth effect in celiac disease autoimmunity to gain novel insights into the early pathogenesis of celiac disease. Interactions between season of birth, genetics, and early-life environmental factors on the risk of celiac autoimmunity were investigated in the multicenter TEDDY birth cohort study.

Protocol for the Australian Type 1 Diabetes National Screening Pilot: Assessing the feasibility and acceptability of three general population screening models in children.

Aim: One third of Australian children diagnosed with type 1 diabetes present with life-threatening diabetic ketoacidosis (DKA) at diagnosis. Screening for early-stage, presymptomatic type 1 diabetes, with ongoing follow-up, can substantially reduce this risk (<5% risk). Several screening models are being trialled internationally, without consensus on the optimal approach.

Early Appearance of Thyroid Autoimmunity in Children Followed From Birth for Type 1 Diabetes Risk.

Context: Autoantibodies to thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) define preclinical autoimmune thyroid disease (AITD), which can progress to either clinical hypothyroidism or hyperthyroidism.

Objective: We determined the age at seroconversion in children genetically at risk for type 1 diabetes.

Methods: TPOAb and TgAb seropositivity were determined in 5066 healthy children with human leukocyte antigen (HLA) DR3- or DR4-containing haplogenotypes from The Environmental Determinants of Diabetes in the Young (TEDDY) study.

Islet autoantibody frequency in relatives of children with type 1 diabetes who have a type 2 diabetes diagnosis.

Aim: This study aimed to evaluate characteristics of autoimmunity in individuals who have a type 2 diagnosis and are relatives of children with type 1 diabetes.

Methods: Pre-diagnosis samples (median 17 months before onset) from relatives who were later diagnosed with type 2 diabetes were measured for autoantibodies to glutamate decarboxylase 65 (GADA), islet antigen-2 (IA-2A), zinc transporter 8 (ZnT8A) and insulin (IAA) as well as the type 1 diabetes genetic risk score (GRS2). Associations between islet autoantibodies, insulin treatment and GRS2 were analysed using Fisher's exact and t-tests.

Consensus Guidance for Monitoring Individuals With Islet Autoantibody-Positive Pre-Stage 3 Type 1 Diabetes.

Given the proven benefits of screening to reduce diabetic ketoacidosis (DKA) likelihood at the time of stage 3 type 1 diabetes diagnosis, and emerging availability of therapy to delay disease progression, type 1 diabetes screening programs are being increasingly emphasized. Once broadly implemented, screening initiatives will identify significant numbers of islet autoantibody-positive (IAb+) children and adults who are at risk for (confirmed single IAb+) or living with (multiple IAb+) early-stage (stage 1 and stage 2) type 1 diabetes. These individuals will need monitoring for disease progression; much of this care will happen in nonspecialized settings.

Consensus guidance for monitoring individuals with islet autoantibody-positive pre-stage 3 type 1 diabetes.

Given the proven benefits of screening to reduce diabetic ketoacidosis (DKA) likelihood at the time of stage 3 type 1 diabetes diagnosis, and emerging availability of therapy to delay disease progression, type 1 diabetes screening programmes are being increasingly emphasised. Once broadly implemented, screening initiatives will identify significant numbers of islet autoantibody-positive (IAb) children and adults who are at risk of (confirmed single IAb) or living with (multiple IAb) early-stage (stage 1 and stage 2) type 1 diabetes. These individuals will need monitoring for disease progression; much of this care will happen in non-specialised settings.

The Influence of Pubertal Development on Autoantibody Appearance and Progression to Type 1 Diabetes in the TEDDY Study.

Context: The 2 peaks of type 1 diabetes incidence occur during early childhood and puberty.

Objective: We sought to better understand the relationship between puberty, islet autoimmunity, and type 1 diabetes.

Methods: The relationships between puberty, islet autoimmunity, and progression to type 1 diabetes were investigated prospectively in children followed in The Environmental Determinants of Diabetes in the Young (TEDDY) study.

Data-Driven Phenotyping of Presymptomatic Type 1 Diabetes Using Longitudinal Autoantibody Profiles.

Objective: To characterize distinct islet autoantibody profiles preceding stage 3 type 1 diabetes.

Research Design And Methods: The T1DI (Type 1 Diabetes Intelligence) study combined data from 1,845 genetically susceptible prospectively observed children who were positive for at least one islet autoantibody: insulin autoantibody (IAA), GAD antibody (GADA), or islet antigen 2 antibody (IA-2A). Using a novel similarity algorithm that considers an individual's temporal autoantibody profile, age at autoantibody appearance, and variation in the positivity of autoantibody types, we performed an unsupervised hierarchical clustering analysis.

Caesarean section and risk of type 1 diabetes.

Aims/hypothesis: Delivery by Caesarean section continues to rise globally and has been associated with the risk of developing type 1 diabetes and the rate of progression from pre-symptomatic stage 1 or 2 type 1 diabetes to symptomatic stage 3 disease. The aim of this study was to examine the association between Caesarean delivery and progression to stage 3 type 1 diabetes in children with pre-symptomatic early-stage type 1 diabetes.

Methods: Caesarean section was examined in 8135 children from the TEDDY study who had an increased genetic risk for type 1 diabetes and were followed from birth for the development of islet autoantibodies and type 1 diabetes.

Intake of B vitamins and the risk of developing islet autoimmunity and type 1 diabetes in the TEDDY study.

Purpose: The aim was to study the association between dietary intake of B vitamins in childhood and the risk of islet autoimmunity (IA) and progression to type 1 diabetes (T1D) by the age of 10 years.

Methods: We followed 8500 T1D-susceptible children born in the U.S.

Clinical Prediction Models Combining Routine Clinical Measures Have High Accuracy in Identifying Youth-Onset Type 2 Diabetes Defined by Maintained Endogenous Insulin Secretion: The SEARCH for Diabetes in Youth Study.

Objective: With high prevalence of obesity and overlapping features between diabetes subtypes, accurately classifying youth-onset diabetes can be challenging. We aimed to develop prediction models that, using characteristics available at diabetes diagnosis, can identify youth who will retain endogenous insulin secretion at levels consistent with type 2 diabetes (T2D).

Research Design And Methods: We studied 2,966 youth with diabetes in the prospective SEARCH for Diabetes in Youth study (diagnosis age ≤19 years) to develop prediction models to identify participants with fasting C-peptide ≥250 pmol/L (≥0.

Distinct transcriptomic profiles in children prior to the appearance of type 1 diabetes-linked islet autoantibodies and following enterovirus infection.

Although the genetic basis and pathogenesis of type 1 diabetes have been studied extensively, how host responses to environmental factors might contribute to autoantibody development remains largely unknown. Here, we use longitudinal blood transcriptome sequencing data to characterize host responses in children within 12 months prior to the appearance of type 1 diabetes-linked islet autoantibodies, as well as matched control children. We report that children who present with insulin-specific autoantibodies first have distinct transcriptional profiles from those who develop GADA autoantibodies first.

Diabetes Study of Children of Diverse Ethnicity and Race: Study design.

Aims: Determining diabetes type in children has become increasingly difficult due to an overlap in typical characteristics between type 1 diabetes (T1D) and type 2 diabetes (T2D). The Diabetes Study in Children of Diverse Ethnicity and Race (DISCOVER) programme is a National Institutes of Health (NIH)-supported multicenter, prospective, observational study that enrols children and adolescents with non-secondary diabetes. The primary aim of the study was to develop improved models to differentiate between T1D and T2D in diverse youth.

Clinical prediction models combining routine clinical measures identify participants with youth-onset diabetes who maintain insulin secretion in the range associated with type 2 diabetes: The SEARCH for Diabetes in Youth Study.

Objective: With the high prevalence of pediatric obesity and overlapping features between diabetes subtypes, accurately classifying youth-onset diabetes can be challenging. We aimed to develop prediction models that, using characteristics available at diabetes diagnosis, can identify youth who will retain endogenous insulin secretion at levels consistent with type 2 diabetes (T2D).

Methods: We studied 2,966 youth with diabetes in the prospective SEARCH study (diagnosis age ≤19 years) to develop prediction models to identify participants with fasting c-peptide ≥250 pmol/L (≥0.

Dietary Intake and Body Mass Index Influence the Risk of Islet Autoimmunity in Genetically At-Risk Children: A Mediation Analysis Using the TEDDY Cohort.

Background/objective: Growth and obesity have been associated with increased risk of islet autoimmunity (IA) and progression to type 1 diabetes. We aimed to estimate the effect of energy-yielding macronutrient intake on the development of IA through BMI.

Research Design And Methods: Genetically at-risk children ( = 5,084) in Finland, Germany, Sweden, and the USA, who were autoantibody negative at 2 years of age, were followed to the age of 8 years, with anthropometric measurements and 3-day food records collected biannually.

Gastrointestinal Infections Modulate the Risk for Insulin Autoantibodies as the First-Appearing Autoantibody in the TEDDY Study.

Objective: To investigate gastrointestinal infection episodes (GIEs) in relation to the appearance of islet autoantibodies in The Environmental Determinants of Diabetes in the Young (TEDDY) cohort.

Research Design And Methods: GIEs on risk of autoantibodies against either insulin (IAA) or GAD (GADA) as the first-appearing autoantibody were assessed in a 10-year follow-up of 7,867 children. Stool virome was characterized in a nested case-control study.

HLA Genotype and Probiotics Modify the Association Between Timing of Solid Food Introduction and Islet Autoimmunity in the TEDDY Study.

Objective: To study the interaction among HLA genotype, early probiotic exposure, and timing of complementary foods in relation to risk of islet autoimmunity (IA).

Research Design And Methods: The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively follows 8,676 children with increased genetic risk of type 1 diabetes. We used a Cox proportional hazards regression model adjusting for potential confounders to study early feeding and the risk of IA in a sample of 7,770 children.

Plasma protein biomarkers predict the development of persistent autoantibodies and type 1 diabetes 6 months prior to the onset of autoimmunity.

Type 1 diabetes (T1D) results from autoimmune destruction of β cells. Insufficient availability of biomarkers represents a significant gap in understanding the disease cause and progression. We conduct blinded, two-phase case-control plasma proteomics on the TEDDY study to identify biomarkers predictive of T1D development.

Possible heterogeneity of initial pancreatic islet beta-cell autoimmunity heralding type 1 diabetes.

The etiology of type 1 diabetes (T1D) foreshadows the pancreatic islet beta-cell autoimmune pathogenesis that heralds the clinical onset of T1D. Standardized and harmonized tests of autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA), islet antigen-2 (IA-2A), and ZnT8 transporter (ZnT8A) allowed children to be followed from birth until the appearance of a first islet autoantibody. In the Environmental Determinants of Diabetes in the Young (TEDDY) study, a multicenter (Finland, Germany, Sweden, and the United States) observational study, children were identified at birth for the T1D high-risk HLA haploid genotypes DQ2/DQ8, DQ2/DQ2, DQ8/DQ8, and DQ4/DQ8.

Physical Activity and the Development of Islet Autoimmunity and Type 1 Diabetes in 5- to 15-Year-Old Children Followed in the TEDDY Study.

Objective: This study investigated physical activity and its association with the development of islet autoimmunity and type 1 diabetes in genetically at-risk children aged 5-15 years.

Research Design And Methods: As part of the longitudinal Environmental Determinants of Diabetes in the Young (TEDDY) study, annual assessment of activity using accelerometry was conducted from age 5 years. Time-to-event analyses using Cox proportional hazard models were used to assess the association between time spent in moderate to vigorous physical activity per day and the appearance of one or several autoantibodies and progression to type 1 diabetes in three risk groups: 1) 3,869 islet autoantibody (IA)-negative children, of whom 157 became single IA positive; 2) 302 single IA-positive children, of whom 73 became multiple IA positive; and 3) 294 multiple IA-positive children, of whom 148 developed type 1 diabetes.