Association of Amino-Terminal-Specific Antiglutamate Decarboxylase (GAD65) Autoantibodies with β-Cell Functional Reserve and a Milder Clinical Phenotype in Patients with GAD65 Antibodies and Ketosis-Prone Diabetes Mellitus

Context: We previously characterized patients presenting with diabetic ketoacidosis prospectively into four subgroups of ketosis-prone diabetes mellitus (KPDM), based on the presence or absence of β-cell autoimmunity (A+ or A−) and β-cell functional reserve (B+ or B−). The A+B− KPDM subgroup comprises patients with classic, autoimmune type 1 diabetes, whereas the A+B+ KPDM subgroup has only partial β-cell loss and a distinct clinical phenotype. Objective: We hypothesized that epitope specificity of autoantibodies directed against the 65-kDa isoform of glutamate decarboxylase (GAD65) reflects differences in β-cell destruction. Design: Sera of sequential GAD65Ab-positive KPDM patients admitted for diabetic ketoacidosis (n = 36) were analyzed for their epitope recognition using five GAD65-specific recombinant Fab and their ability to inhibit GAD65 enzymatic activity. All patients were followed longitudinally to assess β-cell functional reserve and insulin dependence. Results: Binding to an amino-terminal epi...