Trialnet

CONTEXT: The presence of islet autoimmunity identifies individuals likely to progress to clinical type 1 diabetes (T1D). In clinical research studies, autoantibody screening followed by regular metabolic monitoring every 6 months reduces incidence of diabetic ketoacidosis (DKA) at diagnosis. OBJECTIVE: We hypothesized that DKA reduction can be achieved on a population basis with a reduced frequency of metabolic monitoring visits. We reasoned that prolonged time between the development of T1D and the time of clinical diagnosis ("undiagnosed time") would more commonly result in DKA and thus that limiting undiagnosed time would decrease DKA...

AIMS: Islet autoantibody screening of infants and young children in the Northern Hemisphere, together with semi-annual metabolic monitoring, is associated with a lower risk of ketoacidosis (DKA) and improved glucose control after diagnosis of clinical (stage 3) type 1 diabetes (T1D). We aimed to determine if similar benefits applied to older Australians and New Zealanders monitored less rigorously. METHODS: DKA occurrence and metabolic control were compared between T1D relatives screened and monitored for T1D and unscreened individuals diagnosed in the general population, ascertained from the Australasian Diabetes Data Network...

OBJECTIVE: Biomarkers predicting risk of type 1 diabetes (stage 3) among children with islet autoantibodies are greatly needed to prevent diabetic ketoacidosis and facilitate prevention therapies. RESEARCH DESIGN AND METHODS: Children in the prospective The Environmental Determinants of Diabetes in the Young (TEDDY) study (n = 707) with confirmed diabetes-associated autoantibodies (GAD antibody, IA-2A, and/or insulin autoantibody) and two or more HbA1c measurements were followed to diabetes or median age 11...

OBJECTIVE: To define the relationship between glucose and C-peptide during the progression to type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: We longitudinally studied glucose and C-peptide response curves (GCRCs), area under curve (AUC) for glucose, and AUC C-peptide from oral glucose tolerance tests (OGTTs), and Index60 (which integrates OGTT glucose and C-peptide values) in Diabetes Prevention Trial-Type 1 (DPT-1) (n = 72) and TrialNet Pathway to Prevention Study (TNPTP) (n = 82) participants who had OGTTs at baseline and follow-up time points before diagnosis...

AIMS/HYPOTHESIS: A HbA1c range of ≥5.7% to <6.5% (39-46 mmol/mol) indicates prediabetes according to American Diabetes Association (ADA) guidelines, yet its identification of individuals with prediabetes specific for type 1 diabetes has not been assessed. A composite glucose and C-peptide measure, Index60, identifies individuals at high risk for type 1 diabetes. We compared Index60 and HbA1c thresholds as markers for type 1 diabetes risk. METHODS: TrialNet Pathway to Prevention study participants with ≥2 autoantibodies (GADA, IAA, IA2A, or ZnT8A) who had oral glucose tolerance tests (OGTT) and HbA1c measurements underwent 1) predictive time-dependent modeling of type 1 diabetes risk (n=2,776) and 2) baseline comparisons between high-risk mutually exclusive groups: Index60≥2...

The development of medical products that can delay or prevent progression to stage 3 type 1 diabetes faces many challenges. Of note, optimising patient selection for type 1 diabetes prevention clinical trials is hindered by significant patient heterogeneity and a lack of characterisation of the time-varying probability of progression to stage 3 type 1 diabetes in individuals positive for two or more islet autoantibodies. To meet these needs, the Critical Path Institute's Type 1 Diabetes Consortium was launched in 2017 as a pre-competitive public-private partnership between stakeholders from the pharmaceutical industry, patient advocacy groups, philanthropic organisations, clinical researchers, the National Institutes of Health and the Food and Drug Administration...

CONTEXT: Decreased first-phase insulin response (FPIR) during intravenous glucose tolerance testing (IVGTT) is an early indicator of β-cell dysfunction and predictor of type 1 diabetes (T1D). OBJECTIVE: Assess whether oral glucose tolerance test (OGTT) measures could serve as FPIR alternatives in their ability to predict T1D in autoantibody positive (Aab+) subjects. DESIGN: OGTT and IVGTT were performed within 30 days of each other. Eleven OGTT variables were evaluated for: 1) correlation with FPIR, and 2) T1D prediction...

Most screening programs to identify individuals at risk for type 1 diabetes have targeted relatives of people living with the disease to improve yield and feasibility. However, ∼90% of those who develop type 1 diabetes do not have a family history. Recent successes in disease-modifying therapies to impact the course of early-stage disease have ignited the consideration of the need for and feasibility of population screening to identify those at increased risk. Existing population screening programs rely on genetic or autoantibody screening, and these have yielded significant information about disease progression and approaches for timing for screening in clinical practice...

AIMS/HYPOTHESIS: Age is known to be one of the most important stratifiers of disease progression in type 1 diabetes. However, what drives the difference in rate of progression between adults and children is poorly understood. Evidence suggests that many type 1 diabetes disease predictors do not have the same effect across the age spectrum. Without a comprehensive analysis describing the varying risk profiles of predictors over the age continuum, researchers and clinicians are susceptible to inappropriate assessment of risk when examining populations of differing ages...

OBJECTIVE: We assessed whether Index60, a composite measure of fasting C-peptide, 60-min C-peptide, and 60-min glucose, could improve the metabolic staging of type 1 diabetes for progression to clinical disease (stage 3) among autoantibody-positive (Ab+ ) individuals with normal 2-h glucose values (<140 mg/dL). RESEARCH DESIGN AND METHODS: We analyzed 3,058 Type 1 Diabetes TrialNet Pathway to Prevention participants with 2-h glucose <140 mg/dL and Index60 <1...

OBJECTIVE: ECL assays are high-affinity autoantibody (Ab) tests that are more specific than Abs detected by traditional radiobinding assays (RBA) for risk screening and prediction of progression to type 1 diabetes. We sought to characterize the association of high-risk HLA haplotypes and genotypes with electrochemiluminescence (ECL) positivity and levels in relatives of individuals with type 1 diabetes. METHODS: We analyzed 602 participants from the TrialNet Pathway to Prevention Study who were positive for at least one RBA diabetes related Ab (GADA or IAA) and for whom ECL and HLA data were available...

AIMS: Alterations of the exocrine pancreas have been reported in type 1 diabetes, but their contribution to the pathogenesis of the disease is poorly understood. Here, we investigated markers of exocrine pancreas dysfunction in individuals at-risk of developing type 1 diabetes. METHODS: Serum P-amylase and lipase levels were assessed in samples obtained from healthy controls, patients with new onset type 1 diabetes, relatives participating to the TrialNet Pathway to Prevention who were, at blood collection, autoantibody negative or positive for a single autoantibody (low-risk individuals), and positive for multiple autoantibodies (high-risk individuals)...

AIMS/HYPOTHESIS: Methods to identify individuals at highest risk for type 1 diabetes are essential for the successful implementation of disease-modifying interventions. Simple metabolic measures are needed to help stratify autoantibody-positive (Aab+) individuals who are at risk of developing type 1 diabetes. HOMA2-B is a validated mathematical tool commonly used to estimate beta cell function in type 2 diabetes using fasting glucose and insulin. The utility of HOMA2-B in association with type 1 diabetes progression has not been tested...

End points that provide an early identification of treatment effects are needed to implement type 1 diabetes prevention trials more efficiently. To this end, we assessed whether metabolic end points can be used to detect a teplizumab effect on rapid β-cell decline within 3 months after treatment in high-risk individuals in the TrialNet teplizumab trial. Glucose and C-peptide response curves (GCRCs) were constructed by plotting mean glucose and C-peptide values from 2-h oral glucose tolerance tests on a two-dimensional grid...

OBJECTIVE: To assess the progression of type 1 diabetes using time to peak glucose or C-peptide during oral glucose tolerance tests (OGTTs) in autoantibody-positive relatives of people with type 1 diabetes. RESEARCH DESIGN AND METHODS: We examined 2-h OGTTs of participants in the Diabetes Prevention Trial Type 1 (DPT-1) and TrialNet Pathway to Prevention (PTP) studies. We included 706 DPT-1 participants (mean ± SD age, 13.84 ± 9.53 years; BMI Z-score, 0.33 ± 1...

AIMS/HYPOTHESIS: Accurate prediction of disease progression in individuals with pre-symptomatic type 1 diabetes has potential to prevent ketoacidosis and accelerate development of disease-modifying therapies. Current tools for predicting risk require multiple blood samples taken during an OGTT. Our aim was to develop and validate a simpler tool based on a single blood draw. METHODS: Models to predict disease progression using a single OGTT time point (0, 30, 60, 90 or 120 min) were developed using TrialNet data collected from relatives with type 1 diabetes and validated in independent populations at high genetic risk of type 1 diabetes (TrialNet, Diabetes Prevention Trial-Type 1, The Environmental Determinants of Diabetes in the Young [1]) and in a general population of Bavarian children who participated in Fr1da...

OBJECTIVE: We aimed to test whether type 2 diabetes (T2D)-associated TCF7L2 genetic variants affect insulin sensitivity or secretion in autoantibody-positive relatives at risk for type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: We studied autoantibody-positive TrialNet Pathway to Prevention study participants ( N = 1,061) (mean age 16.3 years) with TCF7L2 single nucleotide polymorphism (SNP) information and baseline oral glucose tolerance test (OGTT) to calculate indices of insulin sensitivity and secretion...

Objective: Biomarkers are needed to characterize heterogeneity within populations at risk for type 1 diabetes. The ratio of proinsulin to C-peptide (PI:C ratio), has been proposed as a biomarker of beta cell dysfunction and is associated with progression to type 1 diabetes. However, relationships between PI:C ratios and autoantibody type and number have not been examined. We sought to characterize PI:C ratios in multiple islet autoantibody positive, single autoantibody positive and autoantibody negative relatives of individuals with type 1 diabetes...

We analyzed the effects of a single 14-day course of teplizumab treatment on metabolic function and immune cells among participants in a previously reported randomized controlled trial of nondiabetic relatives at high risk for type 1 diabetes (T1D). In an extended follow-up (923-day median) of a previous report of teplizumab treatment, we found that the median times to diagnosis were 59.6 and 27.1 months for teplizumab- and placebo-treated participants, respectively (HR = 0.457, P = 0.01). Fifty percent of teplizumab-treated but only 22% of the placebo-treated remained diabetes-free...

AIMS/HYPOTHESIS: We aimed to compare characteristics of individuals identified in the peri-diagnostic range by Index60 (composite glucose and C-peptide measure) ≥2.00, 2 h OGTT glucose ≥11.1 mmol/l, or both. METHODS: We studied autoantibody-positive participants in the Type 1 Diabetes TrialNet Pathway to Prevention study who, at their baseline OGTT, had 2 h blood glucose ≥11.1 mmol/l and/or Index60 ≥2.00 (n = 354, median age = 11.2 years, age range = 1...