Context: We previously characterized patients presenting with diabetic ketoacidosis (DKA) prospectively into 4 subgroups of "ketosis-prone diabetes mellitus" (KPDM), based on the presence or absence of cell autoimmunity ("A+" or "A-") and 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 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 cell destruction.

Design: Sera of sequential GAD65AB-positive KPDM patients admitted for DKA (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 cell functional reserve and insulin dependence.

Results: Binding to an amino-terminal epitope defined by monoclonal antibody DPD correlated positively with fasting serum C-peptide levels at baseline (P = 0.0008) and after 1 yr (P = 0.007). Binding to the DPD-defined epitope also correlated positively with area under the curve for C-peptide following glucagon stimulation (P = 0.007) and with HOMA%B at 1 yr (P = 0.03). Binding to the DPD-defined epitope was significantly stronger in A+B+ than in A+B- patients (P = 0.001). Sera of 16 patients (44%) significantly inhibited GAD65 enzymatic activity, but this did not correlate with cell function.

Conclusion: DPD-defined epitope specificity is correlated directly with preserved cell functional reserve in GAD65AB-positive patients, and is associated with the milder clinical phenotype of A+B+ KPDM.