title: 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.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  Adult KPD patients (n = 384) were followed longitudinally in a research clinic.
  
  
  METHODS
  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.
authors.affiliation: University of Washington (S.O., L.K.G., J.R., C.S.H.), Seattle, Washington 98109; and Diabetes Research Center (R.P., D.I., N.R., R.G., A.B.), Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, and Endocrine Service (N.R., R.G., A.B.), Ben Taub General Hospital, Houston, Texas 77030.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Oak
authors.forename: Lakshmi K
authors.initials: LK
authors.lastname: Gaur
authors.forename: Jared
authors.initials: J
authors.lastname: Radtke
authors.forename: Roshni
authors.initials: R
authors.lastname: Patel
authors.forename: Dinakar
authors.initials: D
authors.lastname: Iyer
authors.forename: Nalini
authors.initials: N
authors.lastname: Ram
authors.forename: Ruchi
authors.initials: R
authors.lastname: Gaba
authors.forename: Ashok
authors.initials: A
authors.lastname: Balasubramanyam
authors.forename: Christiane S
authors.initials: CS
authors.lastname: Hampe
mesh_terms: D000328:Adult; D001323:Autoantibodies / Q000097:blood*; D002452:Cell Count; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000276:immunology / Q000503:physiopathology; D016883:Diabetic Ketoacidosis / Q000097:blood* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D018604:Epitope Mapping; D000939:Epitopes / Q000276:immunology; D005500:Follow-Up Studies; D005968:Glutamate Decarboxylase / Q000737:chemistry / Q000276:immunology*; D006239:Haplotypes; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D050417:Insulin-Secreting Cells / Q000473:pathology* / Q000502:physiology
chemical_list: D001323:Autoantibodies; D000939:Epitopes; D000949:Histocompatibility Antigens Class II; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2