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OBJECTIVE Autoantibodies directed against tyrosine phosphatase IA-2 antibody (IA-2 Ab) are diagnostic for autoimmune type 1 diabetes. Conventional assays target the intracellular domain of IA-2. Among patients with ketosis-prone diabetes (KPD), characterized by presentation with diabetic ketoacidosis (DKA), &amp;gt;60% of adults lack three classic islet autoantibodies—IA-2, GAD65, and ZnT8 Abs—associated with type 1 diabetes. We aimed to determine whether apparently autoantibody-negative (“A−”) KPD patients possess occult IA-2 Ab directed against full-length IA-2 (IA-2FL) or its extracellular domain (IA-2EC). RESEARCH DESIGN AND METHODS We developed an assay that targets IA-2FL and IA-2EC and used it to analyze 288 subjects with A− KPD. RESULTS Ten A− KPD patients were positive for IA-2EC Ab (3.5%), and three were also positive for IA-2FL Ab (1.0%), similar to frequencies in type 1 and type 2 diabetes. CONCLUSIONS Measurement of IA-2FL Ab and IA-2EC Ab improves the accuracy of the Aβ classification of KPD patients.

Autoantibodies to the IA-2 Extracellular Domain Refine the Definition of “A+” Subtypes of Ketosis-Prone Diabetes