Association of amino-terminal-specific antiglutamate decarboxylase (GAD65) autoantibodies with beta-cell functional reserve and a milder clinical phenotype in patients with GAD65 antibodies and ketosis-prone diabetes mellitus

J Clin Endocrinol Metab. 2007 Feb;92(2):462-7. doi: 10.1210/jc.2006-1719. Epub 2006 Nov 7.


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 beta-cell autoimmunity (A+ or A-) and beta-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 beta-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 beta-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 beta-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 beta-cell function.

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antibody Specificity
  • Autoantibodies / blood
  • Autoantibodies / immunology*
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetic Ketoacidosis / immunology*
  • Enzyme Activation / immunology
  • Epitopes / immunology
  • Epitopes / metabolism
  • Female
  • Glutamate Decarboxylase / immunology*
  • Glutamate Decarboxylase / metabolism
  • Humans
  • Insulin-Secreting Cells / immunology*
  • Isoenzymes / immunology*
  • Isoenzymes / metabolism
  • Male
  • Middle Aged
  • Phenotype
  • Radioligand Assay
  • Severity of Illness Index
  • Sulfur Radioisotopes


  • Autoantibodies
  • Epitopes
  • Isoenzymes
  • Sulfur Radioisotopes
  • Glutamate Decarboxylase
  • glutamate decarboxylase 2