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

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.

• Authors: Shilpa Oak, Lakshmi K Gaur, Jared Radtke, Roshni Patel, Dinakar Iyer, Nalini Ram, Ruchi Gaba, Ashok Balasubramanyam, Christiane S Hampe
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 99 Issue 6 Pg. E1040-4 (Jun 2014) ISSN: 1945-7197 [Electronic] United States
• PMID: 24601691 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

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

Topics

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