Masked and overt autoantibodies specific to the DPD epitope of 65-kDa glutamate decarboxylase (GAD65-DPD) are associated with preserved β-cell functional reserve in ketosis-prone diabetes

J Clin Endocrinol Metab. 2014 Jun;99(6):E1040-4. doi: 10.1210/jc.2013-4189. Epub 2014 Mar 6.


Context: Ketosis-prone diabetes (KPD), defined by presentation with diabetic ketoacidosis (DKA), comprises 4 subgroups based on the presence or absence of islet cell autoantibodies (A(-) or A(+)) and β-cell functional reserve (β(-) or β(+)). Among A(+) KPD, autoantibody epitope reactivity to 65-kDa glutamate decarboxylase (GAD65), defined by monoclonal GAD65Ab(DPD), was associated with greater β-cell functional reserve. In a majority of healthy individuals, GAD65Ab are present in the sera but are masked by anti-idiotypic antibodies; in contrast, overtly GAD65Ab-positive patients with autoimmune type 1 diabetes patients lack these anti-idiotypic antibodies.

Objective: Our objective was to determine the presence of masked and overt GAD65Ab(DPD) in relation to β-cell function and genetic risk factors in KPD patients.

Design: We investigated the associations of masked and overt GAD65Ab(DPD) with β-cell functional reserve, and their relationship with human leukocyte antigen (HLA) class II haplotypes linked to autoimmune diabetes susceptibility or resistance, in a large KPD cohort.

Patients: Adult KPD patients (n = 384) were followed longitudinally in a research clinic.

Main outcome measures: β-Cell function, autoantibody status, GAD65Ab epitopes, and HLA class II haplotypes were evaluated.

Results: Overall, KPD patients with β-cell functional reserve (β(+) subgroups) showed significantly higher frequency of masked GAD65Ab(DPD) than patients without β-cell functional reserve (β(-) subgroups): 112 of 144 (79%) compared with 59 of 100 (59%), respectively (P = .002). Masked or overt GAD65Ab(DPD) were also more frequent among autoantibody-positive patients with preserved β-cell functional reserve (A(+)β(+) KPD) than those lacking β-cell function (A(+)β(-) KPD): 77% compared with 55% (P = .01). The susceptibility HLA haplotypes DQA1*0301/DQB1*0302 and DQA1*0301/DQB1*0201 were associated with absence of overt or masked GAD65Ab(DPD) (odds Ratios 2.3 and 2.2, respectively).

Conclusions: Masked GAD65Ab(DPD) are strongly associated with preserved β-cell functional reserve among patients with KPD. Absence of GAD65Ab(DPD) reactivity is associated with 2 HLA class II susceptibility haplotypes for autoimmune type 1 diabetes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Autoantibodies / blood*
  • Cell Count
  • Diabetes Mellitus, Type 1 / complications
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / physiopathology
  • Diabetic Ketoacidosis / blood*
  • Diabetic Ketoacidosis / immunology
  • Diabetic Ketoacidosis / pathology
  • Diabetic Ketoacidosis / physiopathology
  • Epitope Mapping
  • Epitopes / immunology
  • Follow-Up Studies
  • Glutamate Decarboxylase / chemistry
  • Glutamate Decarboxylase / immunology*
  • Haplotypes
  • Histocompatibility Antigens Class II / genetics
  • Humans
  • Insulin-Secreting Cells / pathology*
  • Insulin-Secreting Cells / physiology


  • Autoantibodies
  • Epitopes
  • Histocompatibility Antigens Class II
  • Glutamate Decarboxylase
  • glutamate decarboxylase 2