Abstract
CONTEXT: Type 1 diabetes (T1D) progresses from genetic risk to metabolic disease. Anti-β-cell antibodies (AABs), alongside clinical features, define the stages of T1D and enable identification of presymptomatic individuals. OBJECTIVE: To describe the natural history of patients with ≥1 positive AAB, analyzing progression to stage 3 T1D and clinical severity at diagnosis. DESIGN: Single-center retrospective cohort study (February 2012-April 2025). PATIENTS: One-hundred and six patients with ≥1 AAB-positive enrolled in a structured follow-up program. MAIN OUTCOME MEASURE: progression to stage 3 T1D and occurrence of diabetic ketoacidosis (DKA) at diagnosis. RESULTS: During a median follow-up of 4 years, 19 of 106 AAB-positive patients progressed to stage 3 T1D, none of whom presented with DKA at diagnosis. The 5-year cumulative risk of progression was 16.6% (95% CI: 10.0%-26.9%). Patients with multiple AAB positivity at baseline had a significantly higher 5-year risk than those with a single positive AAB (40.4% vs 8.3%; P = .0002). Glutamic acid decarboxylase (GAD) autoantibody positivity was associated with an increased 5-year risk of progression (25.7% vs 2.8% in GAD-negative children; P = .0063) and remained independently associated with T1D onset in multivariable analysis. CONCLUSION: Persistent autoantibody positivity, particularly for GAD, is strongly associated with progression to stage 3 T1D. Children identified through AAB monitoring show a milder clinical presentation at diagnosis, with no cases of DKA. These data support screening and structured follow-up of at-risk children, which may help prevent DKA and facilitate identification of candidates for disease-modifying interventions.