Predictive Autoantibodies Before the Diagnosis of Type I Diabetes in Adults

Recent epidemiologic studies indicate that adult-onset type 1 diabetes (AOT1D) is more common than childhood-onset type 1 diabetes, yet it remains clinically underrecognized. Because little is known about the emergence of islet autoantibodies in AOT1D, we conducted a retrospective study using electronic medical records from the United States Military Health System and longitudinal serum samples from 169 individuals with AOT1D and 40 healthy controls obtained from the Department of Defense Serum Repository. Among 643 prediagnostic samples from individuals with AOT1D, IA-2 autoantibodies were the most prevalent (50%), followed by GADA (46%), IA-2{beta} (34%), ZnT8-R (27%), and ZnT8-W (15%). Overall, 85% (144/169) of subjects were seropositive for at least one autoantibody prior to diagnosis. Analysis of the earliest available sample from all of the AOT1D cases, grouped into 5-year intervals preceding diagnosis, demonstrated a progressive increase in seropositivity over time: 38% of subjects were seropositive more than 20 years before diagnosis, increasing to 44% at 20-15 years, 59% at 15-10 years, 73% at 10-5 years, and 91% within 5 years of diagnosis. Among the 144 seropositive individuals, positivity for two or more autoantibodies was the most common pattern, occurring in 50% (72/144) of cases. Isolated GADA positivity (22%) and isolated IA-2/IA-2{beta} positivity (24%) occurred at similar frequencies, whereas isolated ZnT8 positivity was uncommon (4%). Temporal analysis showed that isolated GADA positivity appeared earliest, with a median onset of 7.9 years before diagnosis, whereas multiple-autoantibody positivity, IA-2 positivity, and ZnT8 positivity emerged later, with median onsets of 4.6, 4.5, and 1.9 years before diagnosis, respectively. These findings extend observations from pediatric type 1 diabetes to adults and demonstrate that AOT1D-associated autoimmunity often begins decades before clinical diagnosis, highlighting a potentially important window for risk stratification and preventive intervention.