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

• Published in: The journal of clinical endocrinology and metabolism 2014-06, Vol.99 (6), p.E1040-E1044
• Main Authors: Oak, Shilpa, Gaur, Lakshmi K, Radtke, Jared, Patel, Roshni, Iyer, Dinakar, Ram, Nalini, Gaba, Ruchi, Balasubramanyam, Ashok, Hampe, Christiane S
• Format: Article
• Language: English
• Subjects: 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; JCEM Online: Brief Reports
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2013-4189

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.