Characteristics of autoantibody-positive individuals without high-risk HLA-DR4-DQ8 or HLA-DR3-DQ2 haplotypes.

Aims/hypothesis: Many studies of type 1 diabetes pathogenesis focus on individuals with high-risk HLA haplotypes. We tested the hypothesis that, among islet autoantibody-positive individuals, lacking HLA-DRB1*04-DQA1*03-DQB1*0302 (HLA-DR4-DQ8) and/or HLA-DRB1*0301-DQA1*0501-DQB1*0201 (HLA-DR3-DQ2) is associated with phenotypic differences, compared with those who have these high-risk HLA haplotypes.

Methods: We classified autoantibody-positive relatives of individuals with type 1 diabetes into four groups based on having both HLA-DR4-DQ8 and HLA-DR3-DQ2 (DR3/DR4; n=1263), HLA-DR4-DQ8 but not HLA-DR3-DQ2 (DR4/non-DR3; n=2340), HLA-DR3-DQ2 but not HLA-DR4-DQ8 (DR3/non-DR4; n=1607) and neither HLA-DR3-DQ2 nor HLA-DR4-DQ8 (DRX/DRX; n=1294).

Identification of type 1 diabetes risk phenotypes using an outcome-guided clustering analysis.

Aims/hypothesis: Although statistical models for predicting type 1 diabetes risk have been developed, approaches that reveal the heterogeneity of the at-risk population by identifying clinically meaningful clusters are lacking. We aimed to identify and characterise clusters of islet autoantibody-positive individuals who share similar characteristics and type 1 diabetes risk.

Methods: We tested a novel outcome-guided clustering method in initially non-diabetic autoantibody-positive relatives of individuals with type 1 diabetes, using the TrialNet Pathway to Prevention study data (n=1123).

Longitudinal changes in DNA methylation during the onset of islet autoimmunity differentiate between reversion versus progression of islet autoimmunity.

Background: Type 1 diabetes (T1D) is preceded by a heterogenous pre-clinical phase, islet autoimmunity (IA). We aimed to identify pre vs. post-IA seroconversion (SV) changes in DNAm that differed across three IA progression phenotypes, those who lose autoantibodies (reverters), progress to clinical T1D (progressors), or maintain autoantibody levels (maintainers).

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.

Lower Prevalence of Diabetic Ketoacidosis at Diagnosis in Research Participants Monitored for Hyperglycemia.

Context: In Colorado children, the prevalence of diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes has been increasing over time.

Objective: To evaluate the prevalence of and factors involved in DKA at type 1 diabetes diagnosis among participants followed in monitoring research studies before diagnosis compared to patients from the community.

Methods: We studied patients < 18 years diagnosed with type 1 diabetes between 2005 and 2021 at the Barbara Davis Center for Diabetes and compared the prevalence of and factors associated with DKA at diagnosis among participants in preclinical monitoring studies vs those diagnosed in the community.

Longitudinal Assessment of Pancreas Volume by MRI Predicts Progression to Stage 3 Type 1 Diabetes.

Objective: This multicenter prospective cohort study compared pancreas volume as assessed by MRI, metabolic scores derived from oral glucose tolerance testing (OGTT), and a combination of pancreas volume and metabolic scores for predicting progression to stage 3 type 1 diabetes (T1D) in individuals with multiple diabetes-related autoantibodies.

Research Design And Methods: Pancreas MRI was performed in 65 multiple autoantibody-positive participants enrolled in the Type 1 Diabetes TrialNet Pathway to Prevention study. Prediction of progression to stage 3 T1D was assessed using pancreas volume index (PVI), OGTT-derived Index60 score and Diabetes Prevention Trial-Type 1 Risk Score (DPTRS), and a combination of PVI and DPTRS.

Type 1 Diabetes Risk Phenotypes Using Cluster Analysis.

Background: Although statistical models for predicting type 1 diabetes risk have been developed, approaches that reveal clinically meaningful clusters in the at-risk population and allow for non-linear relationships between predictors are lacking. We aimed to identify and characterize clusters of islet autoantibody-positive individuals that share similar characteristics and type 1 diabetes risk.

Methods: We tested a novel outcome-guided clustering method in initially non-diabetic autoantibody-positive relatives of individuals with type 1 diabetes, using the TrialNet Pathway to Prevention (PTP) study data (n=1127).

Disease-modifying therapies and features linked to treatment response in type 1 diabetes prevention: a systematic review.

Background: Type 1 diabetes (T1D) results from immune-mediated destruction of insulin-producing beta cells. Prevention efforts have focused on immune modulation and supporting beta cell health before or around diagnosis; however, heterogeneity in disease progression and therapy response has limited translation to clinical practice, highlighting the need for precision medicine approaches to T1D disease modification.

Methods: To understand the state of knowledge in this area, we performed a systematic review of randomized-controlled trials with ≥50 participants cataloged in PubMed or Embase from the past 25 years testing T1D disease-modifying therapies and/or identifying features linked to treatment response, analyzing bias using a Cochrane-risk-of-bias instrument.

Hydroxychloroquine in Stage 1 Type 1 Diabetes.

Objective: Innate immune responses may be involved in the earliest phases of type 1 diabetes (T1D).

Research Design And Methods: To test whether blocking innate immaune cells modulated progression of the disease, we randomly assigned 273 individuals with stage 1 T1D to treatment with hydroxychloroquine (n = 183; 5 mg/kg per day to a maximum of 400 mg) or placebo (n = 90) and assessed whether hydroxychloroquine treatment delayed or prevented progression to stage 2 T1D (i.e.

Historical Insights and Current Perspectives on the Diagnosis and Management of Presymptomatic Type 1 Diabetes.

The article provides practical guidance for (1) interpreting and confirming islet autoantibody screening results for type 1 diabetes (T1D) and (2) follow-up of individuals with early stages of T1D with the goal of ensuring medical safety and providing patients and their families with an assessment of risk for progression to a clinical diagnosis of T1D. We used an explicit a priori methodology to identify areas of agreement and disagreement in how to manage patients with early T1D. We used a modified Delphi method, which is a systematic, iterative approach to identifying consensus.

Anxiety and Risk Perception in Parents of Children Identified by Population Screening as High Risk for Type 1 Diabetes.

Objective: To assess anxiety and risk perception among parents whose children screened positive for islet autoantibodies, indicating elevated risk for type 1 diabetes (T1D).

Research Design And Methods: The Autoimmunity Screening for Kids (ASK) study identified 319 children age 1 to 17 years at risk for T1D via screening for islet autoantibodies; 280 children with confirmed islet autoantibodies and their caregivers enrolled in a follow-up education and monitoring program to prevent diabetic ketoacidosis at diagnosis. Parents completed questionnaires at each monitoring visit, including a 6-item version of the State Anxiety Inventory (SAI), to assess anxiety about their child developing T1D, and a single question to assess risk perception.

OGTT Metrics Surpass Continuous Glucose Monitoring Data for T1D Prediction in Multiple-Autoantibody-Positive Individuals.

Context: The value of continuous glucose monitoring (CGM) for monitoring autoantibody (AAB)-positive individuals in clinical trials for progression of type 1 diabetes (T1D) is unknown.

Objective: Compare CGM with oral glucose tolerance test (OGTT)-based metrics in prediction of T1D.

Methods: At academic centers, OGTT and CGM data from multiple-AAB relatives were evaluated for associations with T1D diagnosis.

Prevalence of SARS-CoV-2 Antibodies Among Healthy Children From Colorado From 2020 to 2021: A Brief Report.

There are few estimates of the seroprevalence of SARS-CoV-2 antibodies among children in the United States. We measured vaccine and infection induced seroprevalence among nearly 5000 healthy 1 to 17-year-old children in Colorado from 2020 to 2021. By December 2021, 89% of older children, ages 12 to 18, had antibodies detected.

Type 1 Diabetes Prevention: a systematic review of studies testing disease-modifying therapies and features linked to treatment response.

Background: Type 1 diabetes (T1D) results from immune-mediated destruction of insulin-producing beta cells. Efforts to prevent T1D have focused on modulating immune responses and supporting beta cell health; however, heterogeneity in disease progression and responses to therapies have made these efforts difficult to translate to clinical practice, highlighting the need for precision medicine approaches to T1D prevention.

Methods: To understand the current state of knowledge regarding precision approaches to T1D prevention, we performed a systematic review of randomized-controlled trials from the past 25 years testing disease-modifying therapies in T1D and/or identifying features linked to treatment response, analyzing bias using a Cochrane-risk-of-bias instrument.

Barriers to Screening: An Analysis of Factors Impacting Screening for Type 1 Diabetes Prevention Trials.

Context: Participants with stage 1 or 2 type 1 diabetes (T1D) qualify for prevention trials, but factors involved in screening for such trials are largely unknown.

Objective: To identify factors associated with screening for T1D prevention trials.

Methods: This study included TrialNet Pathway to Prevention participants who were eligible for a prevention trial: oral insulin (TN-07, TN-20), teplizumab (TN-10), abatacept (TN-18), and oral hydroxychloroquine (TN-22).

CGM Metrics Identify Dysglycemic States in Participants From the TrialNet Pathway to Prevention Study.

Objective: Continuous glucose monitoring (CGM) parameters may identify individuals at risk for progression to overt type 1 diabetes. We aimed to determine whether CGM metrics provide additional insights into progression to clinical stage 3 type 1 diabetes.

Research Design And Methods: One hundred five relatives of individuals in type 1 diabetes probands (median age 16.

Temporal development of T cell receptor repertoires during childhood in health and disease.

T cell receptor (TCR) sequences are exceptionally diverse and can now be comprehensively measured with next-generation sequencing technologies. However, a thorough investigation of longitudinal TCR repertoires throughout childhood in health and during development of a common childhood disease, type 1 diabetes (T1D), has not been undertaken. Here, we deep sequenced the TCR-β chain repertoires from longitudinal peripheral blood DNA samples at 4 time points beginning early in life (median age of 1.

Changes in the Coexpression of Innate Immunity Genes During Persistent Islet Autoimmunity Are Associated With Progression of Islet Autoimmunity: Diabetes Autoimmunity Study in the Young (DAISY).

Longitudinal changes in gene expression during islet autoimmunity (IA) may provide insight into biological processes that explain progression to type 1 diabetes (T1D). We identified individuals from Diabetes Autoimmunity Study in the Young (DAISY) who developed IA, autoantibodies present on two or more visits. Illumina's NovaSeq 6000 was used to quantify gene expression in whole blood.