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).

Early Metabolic Endpoints Identify Persistent Treatment Efficacy in Recent-Onset Type 1 Diabetes Immunotherapy Trials.

Objective: Mixed-meal tolerance test-stimulated area under the curve (AUC) C-peptide at 12-24 months represents the primary end point for nearly all intervention trials seeking to preserve β-cell function in recent-onset type 1 diabetes. We hypothesized that participant benefit might be detected earlier and predict outcomes at 12 months posttherapy. Such findings would support shorter trials to establish initial efficacy.

Comparisons of Metabolic Measures to Predict T1D vs Detect a Preventive Treatment Effect in High-Risk Individuals.

Context: Metabolic measures are frequently used to predict type 1 diabetes (T1D) and to understand effects of disease-modifying therapies.

Objective: Compare metabolic endpoints for their ability to detect preventive treatment effects and predict T1D.

Methods: Six-month changes in metabolic endpoints were assessed for (1) detecting treatment effects by comparing placebo and treatment arms from the randomized controlled teplizumab prevention trial, a multicenter clinical trial investigating 14-day intravenous teplizumab infusion and (2) predicting T1D in the TrialNet Pathway to Prevention natural history study.

HOMA-IR and the Matsuda Index as predictors of progression to type 1 diabetes in autoantibody-positive relatives.

Aim/hypothesis: We assessed whether HOMA-IR and the Matsuda Index are associated with transitions through stages of type 1 diabetes.

Methods: Autoantibody (AAb)-positive relatives of individuals with type 1 diabetes (n=6256) from the TrialNet Pathway to Prevention were studied. Associations of indicators of insulin resistance (HOMA-IR) and insulin sensitivity (Matsuda Index) with BMI percentile (BMIp) and age were assessed with adjustments for measures of insulin secretion, Index60 and insulinogenic index (IGI).

Phenotypes Associated With Zones Defined by Area Under the Curve Glucose and C-peptide in a Population With Islet Autoantibodies.

Objective: Metabolic zones were developed to characterize heterogeneity of individuals with islet autoantibodies.

Research Design And Methods: Baseline 2-h oral glucose tolerance test data from 6,620 TrialNet Pathway to Prevention Study (TNPTP) autoantibody-positive participants (relatives of individuals with type 1 diabetes) were used to form 25 zones from five area under the curve glucose (AUCGLU) rows and five area under the curve C-peptide (AUCPEP) columns. Zone phenotypes were developed from demographic, metabolic, autoantibody, HLA, and risk data.

Persistence of β-Cell Responsiveness for Over Two Years in Autoantibody-Positive Children With Marked Metabolic Impairment at Screening.

Objective: We studied longitudinal differences between progressors and nonprogressors to type 1 diabetes with similar and substantial baseline risk.

Research Design And Methods: Changes in 2-h oral glucose tolerance test indices were used to examine variability in diabetes progression in the Diabetes Prevention Trial-Type 1 (DPT-1) study (n = 246) and Type 1 Diabetes TrialNet Pathway to Prevention study (TNPTP) (n = 503) among autoantibody (Ab)+ children (aged <18.0 years) with similar baseline metabolic impairment (DPT-1 Risk Score [DPTRS] of 6.

Index60 Is Superior to HbA1c for Identifying Individuals at High Risk for Type 1 Diabetes.

Context: HbA1c from ≥ 5.7% to < 6.5% (39-46 mmol/mol) indicates prediabetes according to American Diabetes Association guidelines, yet its identification of prediabetes specific for type 1 diabetes has not been assessed.

Oral Glucose Tolerance Test Measures of First-phase Insulin Response and Their Predictive Ability for Type 1 Diabetes.

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.

Index60 Identifies Individuals at Appreciable Risk for Stage 3 Among an Autoantibody-Positive Population With Normal 2-Hour Glucose Levels: Implications for Current Staging Criteria of Type 1 Diabetes.

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 <1.00 values from baseline oral glucose tolerance tests.

HOMA2-B enhances assessment of type 1 diabetes risk among TrialNet Pathway to Prevention participants.

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 Deterrence of Rapid Metabolic Decline Within 3 Months After Teplizumab Treatment in Individuals at High Risk for Type 1 Diabetes.

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.

Time to Peak Glucose and Peak C-Peptide During the Progression to Type 1 Diabetes in the Diabetes Prevention Trial and TrialNet Cohorts.

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.

Genetic Variants Do Not Influence Insulin Sensitivity or Secretion Indices in Autoantibody-Positive Individuals at Risk for Type 1 Diabetes.

Objective: We aimed to test whether type 2 diabetes (T2D)-associated 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 ( = 1,061) (mean age 16.3 years) with single nucleotide polymorphism (SNP) information and baseline oral glucose tolerance test (OGTT) to calculate indices of insulin sensitivity and secretion.

Baseline Assessment of Circulating MicroRNAs Near Diagnosis of Type 1 Diabetes Predicts Future Stimulated Insulin Secretion.

Type 1 diabetes is an autoimmune disease resulting in severely impaired insulin secretion. We investigated whether circulating microRNAs (miRNAs) are associated with residual insulin secretion at diagnosis and predict the severity of its future decline. We studied 53 newly diagnosed subjects enrolled in placebo groups of TrialNet clinical trials.

The Pathological Evolution of Glucose Response Curves During the Progression to Type 1 Diabetes in the TrialNet Pathway to Prevention Study.

Objective: Glucose response curves (GRCs) during oral glucose tolerance tests (OGTTs) are predictive of type 1 diabetes. We performed a longitudinal analysis in pancreatic autoantibody-positive individuals to assess ) characteristic GRC changes during progression to type 1 diabetes and ) GRC changes in relation to β-cell function changes and to combined glucose and C-peptide response curve (GCRC) changes.

Research Design And Methods: Among antibody-positive individuals with serial OGTTs in the TrialNet Pathway to Prevention study, GRC changes from first to last OGTTs were compared between progressors ( = 298) to type 1 diabetes and nonprogressors ( = 2,216).

One-Hour Oral Glucose Tolerance Tests for the Prediction and Diagnostic Surveillance of Type 1 Diabetes.

Context: Once islet autoantibody-positive individuals are identified, predicting which individuals are at highest risk for type 1 diabetes (T1D) is important. A metabolic risk score derived from 2-hour oral glucose tolerance test (OGTT) data, the Diabetes Prevention Trial-Type 1 risk score (DPTRS), can accurately predict T1D. However, 2-hour OGTTs are time-consuming and costly.

The Effect of Ethnicity in the Rate of Beta-Cell Functional Loss in the First 3 Years After Type 1 Diabetes Diagnosis.

Objective: We set forth to compare ethnicities for metabolic and immunological characteristics at the clinical diagnosis of type 1 diabetes (T1D) and assess the effect of ethnicity on beta-cell functional loss within 3 years after clinical diagnosis.

Research Methods And Design: We studied participants in TrialNet New Onset Intervention Trials (n = 624, median age = 14.4 years, 58% male, 8.

Slowed Metabolic Decline After 1 Year of Oral Insulin Treatment Among Individuals at High Risk for Type 1 Diabetes in the Diabetes Prevention Trial-Type 1 (DPT-1) and TrialNet Oral Insulin Prevention Trials.

We assessed whether oral insulin slowed metabolic decline after 1 year of treatment in individuals at high risk for type 1 diabetes. Two oral insulin trials that did not show efficacy overall and had type 1 diabetes as the primary end point were analyzed: the Diabetes Prevention Trial-Type 1 (DPT-1) and the TrialNet oral insulin trials. Oral glucose tolerance tests at baseline and after 1 year of treatment were analyzed.

Provider-Guided Emergency Support for Persons Living With Type 1 Diabetes During Hurricanes Harvey, Irma, and Maria.

The 2017 Atlantic hurricane season was especially memorable for 3 major hurricanes-Harvey, Irma, and Maria-that devastated population centers across Texas, Florida, and Puerto Rico, respectively. Each storm had unique hazard properties that posed distinctive challenges for persons living with type 1 diabetes (T1D). Diabetes care specialists and educators took on leadership roles for coordinating care and establishing insulin supply lifelines for people with T1D living in the hardest-hit neighborhoods affected by these extreme storms.

The Association Between Heart Rate and Glycemic Status in the National Health and Nutrition Examination Surveys.

Context: Evidence suggests that heart rate (HR) is a prognostic factor for cardiovascular disease (CVD), for which persons with diabetes are at increased risk.

Objective: The objective of this article is to determine the association between HR and glycemic status in a nationally representative sample of US adults, and, among adults with diagnosed diabetes, the association between HR and hemoglobin A1c (HbA1c) level.

Design: A cross-sectional study was conducted.

Early and late C-peptide responses during oral glucose tolerance testing are oppositely predictive of type 1 diabetes in autoantibody-positive individuals.

We examined whether the timing of the C-peptide response during an oral glucose tolerance test (OGTT) in relatives of patients with type 1 diabetes (T1D) is predictive of disease onset. We examined baseline 2-h OGTTs from 670 relatives participating in the Diabetes Prevention Trial-Type 1 (age: 13.8 ± 9.