The implications of autoantibodies to a single islet antigen in relatives with normal glucose tolerance: development of other autoantibodies and progression to type 1 diabetes

Abstract

Aims/hypothesis: Autoantibodies directed at single islet autoantigens are associated with lower overall risk of type 1 diabetes than multiple autoantibodies, but individuals with one autoantibody may progress to higher risk categories. We examined the characteristics of this progression in relatives followed prospectively in the TrialNet Pathway to Prevention.

Methods: The study population comprised 983 relatives who were single autoantibody positive with normal baseline glucose tolerance (median age 16.2 years). Samples were screened for antibodies to GAD, insulinoma-associated antigen 2 (IA-2) and insulin, and all positive samples tested for antibodies to zinc transporter 8 and islet cell antibodies.

Results: Antibodies to at least one additional islet autoantigen appeared in 118 of 983 relatives (overall 5 year risk 22%, 95% CI [17.9, 26.1]). At baseline, antibodies to GAD alone (68%) were more frequent than antibodies to insulin (26%) or IA-2 (6%), but all were associated with a similar risk of developing additional autoantibodies. Risk was associated with younger age (p = 0.002) and HLA class II genotype, but was similar in high and intermediate genetic risk groups (p = 0.65). Relatives who became multiple autoantibody positive during the follow-up had increased risk of developing diabetes comparable with the risk in relatives with multiple autoantibodies at study entry.

Conclusions/interpretation: Progression of islet autoimmunity in single autoantibody positive relatives in late childhood/adult life is associated with a predominance of autoantibodies to GAD and a distinct HLA risk profile. This heterogeneity in type 1 diabetes autoimmunity has potentially important implications for disease prevention.

Keywords: Autoantigens; Diabetes antibodies; GAD; HLA; IA-2; Insulin autoantibodies; Islet autoantibodies; Prediction; Prevention; Zinc transporter 8.

Fig. 1

(a) Time from initial detection of confirmed antibodies to a single islet antigen (GAD, IA-2/ICA512 or insulin) to first detection of confirmed multiple antibodies. The number of individuals at risk at the start of each year of follow-up is shown below each graph. (b) Time from initial detection of confirmed antibodies to a single islet antigen (GAD, IA-2/ICA512 or insulin) to first detection of confirmed multiple antibodies in relatives aged <13 years (black line) and ≥13 years (grey line) (logrank test, p < 0.001). (c) Time from initial detection of confirmed antibodies to a single islet antigen (GAD [black line], IA-2/ICA512 [grey line] or insulin [dashed line]) to first detection of confirmed multiple antibodies (logrank test, p = 0.38)

Fig. 2

(a) Progression to type 1 diabetes in relatives positive for antibodies to GAD (black line), insulin (dashed line) and IA-2/ICA512 (grey line) (logrank test, p = 0.662). (b) Progression to type 1 diabetes in relatives who were confirmed multiple antibody positive at screening (grey line) and those who progressed from confirmed single antibody positive to confirmed multiple antibody positive from the time of progression (black line) (logrank test, p < 0.001)