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

Robert H. Williams Laboratory (C.S.H., T.R.H.), Department of Medicine, University of Washington School of Medicine, Seattle, Washington 98195; Translational Metabolism Unit (R.N., M.R.M., D.I., A.B.), Division of Diabetes, Endocrinology, and Metabolism, Baylor College of Medicine, and Endocrine Service (R.N., G.G., A.B.), Ben Taub General Hospital, Houston, Texas 77030; and Bristol-Myers-Squibb, Co. (M.R.M.), Princeton, New Jersey 08540

Address all correspondence and requests for reprints to: Christiane S. Hampe, Ph.D., Department of Medicine, University of Washington, Seattle, Washington 98195. E-mail: champe{at}u.washington.edu.

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 ß-cell autoimmunity (A+ or A–) and ß-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 ß-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 ß-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 ß-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 after glucagon stimulation (P = 0.007) and with homeostasis model assessment percent 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 ß-cell function.

Conclusion: DPD-defined epitope specificity is correlated directly with preserved ß-cell functional reserve in GAD65Ab-positive patients and is associated with the milder clinical phenotype of A+B+ KPDM.

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