Progression to diabetes in relatives with islet autoantibodies. Is it inevitable?

OBJECTIVE: A large cohort of family members with islet cell antibodies (ICA) > or = 20 Juvenile Diabetes Foundation units (JDF U) was examined to determine whether there was a subgroup at low risk of progression to diabetes; whether risk of progression changed over time; and whether rate of progression to diabetes varied according to age, islet autoantibodies, and genetic markers of susceptibility. RESEARCH DESIGN AND METHODS: Individuals with ICA > or = 20 JDF U were identified from 4,423 family members recruited to prospective family studies in the U.K. Subjects were followed for up to 18 years. Antibodies to insulin, GAD, and IA-2 were measured in the first sample, and HLA class II typing was performed.
RESULTS: Of 147 family members with ICA > or = 20 JDF U on at least one occasion, 29 developed type 1 diabetes after a median of 3.2 years (maximum 18.1). The cumulative risk of developing diabetes within 15 years was 47% (95% CI 28-67) for all family members with ICA > or = 20 JDF U, 2.8% (0-8.2) for those with ICA alone, and 66% (44-87) for those with at least one additional autoantibody marker. There were no differences in age, HLA class II type, or levels of ICA, insulin autoantibodies, or IA-2 antibodies between those who developed diabetes within 5 years of testing and those who developed diabetes after this time. GAD antibody levels we ..., however, higher in those who progressed more slowly.
CONCLUSIONS: Family members with ICA alone are at low risk of progression to diabetes. Rapid development of disease after ICA detection could not be distinguished from delayed development on the basis of autoantibodies or markers of genetic susceptibility, and those with multiple antibodies remained at high risk throughout long-term follow-up. This suggests that all family members with multiple islet autoantibodies are destined to develop autoimmune diabetes.