Single Islet Antigen 2 Antibody-Positive (IA2A Ab+) Children Exhibit Significant Metabolic Abnormalities and 5-Year Type 1 Diabetes (T1D) Risk

Current T1D staging defines multiple Ab+ as the start of T1D (Stage 1 or 2 depending on presence of dysglycemia). However, single Ab+ individuals are considered low-risk and are typically not considered for inclusion in prevention trials. We hypothesized that single IA2A+ children exhibit metabolic compromise with appreciable Stage 3 (clinical diabetes) risk. To test this, we evaluated 2163 confirmed single Ab+ children (IA2A, glutamic acid decarboxylase [GADA], or insulin [IAA]) with available OGTT data in the TrialNet natural history study. With and without age and BMI adjustment (Table), IA2A+ children had higher area under the curve (AUC) glucose, lower AUC C-peptide, and higher diabetes risk indices (Diabetes Prevention Trial Type 1 Risk Score [DPTRS] and Index60). Cox regression demonstrated that IA2A+ children were most likely to have progressed to Stage 3 (50.9% vs. 12.0% or 9.6% over 5 years). Of single Ab+ children who did not progress to Stage 3, GADA+ most frequently progressed to multiple Ab+ (34.0% over 5 years). In conclusion, amongst single Ab+ children, IA2A+ children have greater metabolic dysfunction and rates of progression to Stage 3. These findings suggest that single IA2A+ children exhibit substantial T1D risk, should also be considered as having Stage 1 T1D, and be considered for eligibility in prevention studies. Disclosure E.K.Sims: Speaker's Bureau; Medscape, American Diabetes Association. D.D.Cuthbertson: None. E.Bosi: None. C.Evans-molina: Advisory Panel; Provention Bio, Inc., DiogenX, Avotres Inc., Neurodon, MaiCell Therapeutics, Other Relationship; Isla Technology, Bristol-Myers Squibb Company, Nimbus Therapeutics, Research Support; Lilly, Astellas Pharma Inc. M.J.Redondo: None. B.M.Nathan: None. H.M.Ismail: Consultant; Rise Therapeutics. L.M.Jacobsen: None. J.Sosenko: None.