Single Islet Autoantibody at Diagnosis of Clinical Type 1 Diabetes is Associated With Older Age and Insulin Resistance

Context: Multiple islet autoantibody positivity usually precedes clinical (stage 3) type 1 diabetes (T1D). Objective: To test the hypothesis that individuals who develop stage 3 T1D with only a single autoantibody have unique metabolic differences. Design: Cross-sectional analysis of participants in the T1D TrialNet study. Setting: Autoantibody-positive relatives of individuals with stage 3 T1D. Participants: Autoantibody-positive relatives who developed stage 3 T1D (at median age 12.4 years, range = 1.4-58.6) and had autoantibody data close to clinical diagnosis (n = 786, 47.4% male, 79.9% non-Hispanic white). Main Outcome Measures: Logistic regression modeling was used to assess relationships between autoantibody status and demographic, clinical, and metabolic characteristics, adjusting for potential confounders and correcting for multiple comparisons. Results: At diagnosis of stage 3 T1D, single autoantibody positivity, observed in 119 (15.1%) participants (72% GAD65, 13% microinsulin antibody assay, 11% insulinoma-associated antigen 2, 1% islet cell antibody, 3% autoantibodies to zinc transporter 8 [ZnT8]), was significantly associated with older age, higher C-peptide measures (fasting, area under the curve, 2-hour, and early response in oral glucose tolerance test), higher homeostatic model assessment of insulin resistance, and lower T1D Index60 (all P < 0.03). While with adjustment for age, 2-hour C-peptide remained statistically different, controlling for body mass index (BMI) attenuated the differences. Sex, race, ethnicity, human leukocyte antigen DR3-DQ2, and/or DR4-DQ8, BMI category, and glucose measures were not significantly associated with single autoantibody positivity. Conclusions: Compared with multiple autoantibody positivity, single autoantibody at diagnosis of stage 3 T1D was associated with older age and insulin resistance possibly mediated by elevated BMI, suggesting heterogeneous disease pathogenesis. These differences are potentially relevant for T1D prevention and treatment.