Impact of Age and Antibody Type on Progression From Single to Multiple Autoantibodies in Type 1 Diabetes Relatives

Abstract

Context: Islet autoantibodies are markers of type 1 diabetes, and an increase in number of autoantibodies detected during the preclinical phase predicts progression to overt disease.

Objective: To refine the effect of age in relation to islet antibody type on progression from single to multiple autoantibodies in relatives of people with type 1 diabetes.

Research design and methods: We examined 994 relatives with normal glucose tolerance who were positive for a single autoantibody, followed prospectively in the TrialNet Pathway to Prevention. Antibodies to glutamic acid decarboxylase (GADA), insulin (IAA), insulinoma-associated antigen 2, and zinc transporter 8 and islet cell antibodies were tested every 6 to 12 months. The primary outcome was confirmed development of multiple autoantibodies. Age was categorized as <8 years, 8 to 11 years, 12 to 17 years, and ≥18 years, and optimal age breakpoints were identified by recursive partitioning analysis.

Results: After median follow-up of 2 years, 141 relatives had developed at least one additional autoantibodies. Five-year risk was inversely related to age, but the pattern differed by antibody type: Relatives with GADA showed a gradual decrease in risk over the four age groups, whereas relatives with IAA showed a sharp decrease above age 8 years. Recursive partitioning analysis identified age breakpoints at 14 years in relatives with GADA and at 4 years in relatives with IAA.

Conclusions: In relatives with IAA, spread of islet autoimmunity is largely limited to early childhood, whereas immune responses initially directed at glutamic acid decarboxylase can mature over a longer period. These differences have important implications for monitoring these patients and for designing prevention trials.

Trial registration: ClinicalTrials.gov NCT00097292.

Figure 1.

Particiants who develped additional autoantibodies within 5 years, subdivided by age group. (a) GADA-positive (n = 99) participants. (b) IAA-positive participants (n = 24). Among the relatives who progressed, 17 of 24 (71%) with IAA vs 27 of 99 (27%) with GADA were younger than 8 years of age (P < 0.05).

Figure 2.

Time from initial detection of (a) single GADA to first detection of multiple antibodies in relatives <14 years (black line) and ≥14 years (gray line) and (b) single IAA to first detection of multiple antibodies in relatives <4 years (black line) and ≥4 years (gray line). Aab, autoantibody; Ab, antibody.