title: 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.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Robert H. Williams Laboratory, Department of Medicine, University of Washington, Seattle, Washington 98195, USA. champe@u.washington.edu
authors.forename: Christiane S
authors.initials: CS
authors.lastname: Hampe
authors.forename: Ramaswami
authors.initials: R
authors.lastname: Nalini
authors.forename: Mario R
authors.initials: MR
authors.lastname: Maldonado
authors.forename: Tyler R
authors.initials: TR
authors.lastname: Hall
authors.forename: Gilberto
authors.initials: G
authors.lastname: Garza
authors.forename: Dinakar
authors.initials: D
authors.lastname: Iyer
authors.forename: Ashok
authors.initials: A
authors.lastname: Balasubramanyam
mesh_terms: D000328:Adult; D000368:Aged; D000918:Antibody Specificity; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D016883:Diabetic Ketoacidosis / Q000276:immunology*; D004789:Enzyme Activation / Q000276:immunology; D000939:Epitopes / Q000276:immunology / Q000378:metabolism; D005260:Female; D005968:Glutamate Decarboxylase / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D050417:Insulin-Secreting Cells / Q000276:immunology*; D007527:Isoenzymes / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011869:Radioligand Assay; D012720:Severity of Illness Index; D013462:Sulfur Radioisotopes
chemical_list: D001323:Autoantibodies; D000939:Epitopes; D007527:Isoenzymes; D013462:Sulfur Radioisotopes; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2