Development and recalibration of a multivariable type 1 diabetes prediction model for type 1 diabetes across multiple screening studies.

Background: Accurate type 1 diabetes prediction is important to facilitate screening for pre-clinical type 1 diabetes to enable potential early disease-modifying interventions and to reduce the risk of severe presentation with diabetic ketoacidosis. We aimed to assess the generalisability of a prediction model developed in children followed from birth. Additionally, we sought to create an application for easy calculation and visualisation of individualised risk prediction.

Genetic Risk and Transition through Preclinical Stages of Type 1 Diabetes.

Objective: Our aim was to study the influence of type 1 diabetes (T1D) genetic risk factors on the transition through preclinical stages of T1D.

Methods: In TrialNet participants who have been genotyped with the TEDDY-T1DExomeChip array (Illumina HumanCoreExome Beadarray with custom content), we evaluated the influence of the overall T1D genetic risk score (GRS2), its HLA and non-HLA components, HLA-DR3 and HLA-DR4 haplotypes and 90 single nucleotide polymorphisms previously associated with islet autoimmunity and/or T1D on three transitions between diabetes stages: from single confirmed autoantibody positive to stage 1 (N=4,314), from stage 1 to stage 2 (N=3,066), and from stage 2 to stage 3 (clinical) T1D (N=2,045).

Results: The T1D GRS2 was associated with all three transitions with hazard ratios(HR) of 1.

Prevalence of Islet Autoantibodies in Adults Without Diabetes.

Context: Over half of all new cases of type 1 diabetes (T1D) are diagnosed in adults, yet the natural history of adult-onset T1D, particularly in nonfamilial populations, is not fully understood.

Objective: This study measured the prevalence of islet autoantibodies (IA) in adults without known diabetes and irrespective of T1D family history from Colorado (USA).

Methods: The Autoimmunity Screening for Kids study screened for IAs to insulin, glutamic acid decarboxylase (GADA), islet antigen-2, and zinc transporter 8 in 1087 adults without known diabetes [mean age 40.

Type 1 diabetes prediction in autoantibody-positive individuals: performance, time and money matter.

Aims/hypothesis: Efficient prediction of clinical type 1 diabetes is important for risk stratification and monitoring of autoantibody-positive individuals. In this study, we compared type 1 diabetes predictive models for predictive performance, cost and participant time needed for testing.

Methods: We developed 1943 predictive models using a Cox model based on a type 1 diabetes genetic risk score (GRS2), autoantibody count and types, BMI, age, self-reported gender and OGTT-derived glucose and C-peptide measures.

Review of Monogenic Diabetes: Clinical Features and Precision Medicine in Genetic Forms of Diabetes.

Monogenic diabetes is a group of diseases that encompasses a growing number of genetic abnormalities affecting pancreatic function/development leading to glycemic dysregulation. This includes conditions that have historically been referred to as maturity onset diabetes of the young or MODY in addition to neonatal diabetes mellitus. While recognition of a genetic or inherited form of diabetes has been known for decades, advances in molecular genetic testing have resulted in identification of specific forms of monogenic diabetes.

Exploring Microbiota-Associated Metabolites in Twins Discordant for Type 1 Diabetes.

Objective: Identify microbial and microbiota-associated metabolites in monozygotic (MZ) and dizygotic (DZ) twins discordant for type 1 diabetes (T1D) to gain insight into potential environmental factors that may influence T1D.

Research Design And Methods: Serum samples from 39 twins discordant for T1D were analyzed using a semi-targeted metabolomics approach via liquid chromatography-high-resolution tandem mass spectrometry (LC-HRMS/MS). Statistical analyses identified significant metabolites (p < 0.

A type 1 diabetes prediction model has utility across multiple screening settings with recalibration.

Background: Accurate type 1 diabetes prediction is important to facilitate screening for pre-clinical type 1 diabetes to enable potential early disease-modifying interventions and to reduce the risk of severe presentation with diabetic ketoacidosis. We aimed to assess the generalisability of a prediction model developed in children followed from birth. Additionally, we sought to create an application for easy calculation and visualization of individualized risk prediction.

Continuous glucose monitor metrics from five studies identify participants at risk for type 1 diabetes development.

Aims/hypothesis: We aimed to assess whether continuous glucose monitor (CGM) metrics can accurately predict stage 3 type 1 diabetes diagnosis in those with islet autoantibodies (AAb).

Methods: Baseline CGM data were collected from participants with ≥1 positive AAb type from five studies: ASK (n=79), BDR (n=22), DAISY (n=18), DIPP (n=8) and TrialNet Pathway to Prevention (n=91). Median follow-up time was 2.

Novel T-Cell Reactivities to Hybrid Insulin Peptides in Islet Autoantibody-Positive At-Risk Individuals.

Unlabelled: Type 1 diabetes (T1D) is an autoimmune disease mediated by autoreactive T cells. Our studies indicate that CD4 T cells reactive to hybrid insulin peptides (HIPs) play a critical role in T-cell-mediated β-cell destruction. We have shown that HIPs form in human islets between fragments of the C-peptide and cleavage products of secretory granule proteins.

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.