GAD65Abs Are Not Associated With Beta-Cell Dysfunction in Patients With T2D in the GRADE Study

Authors

Christiane S Hampe
Ali Shojaie
Barbara Brooks-Worrell
Sepideh Dibay
Kristina Utzschneider
Steven E Kahn
Mary E Larkin
Mary L Johnson
Naji Younes
Neda Rasouli
Cyrus Desouza
Robert M Cohen
Jean Y Park
Hermes J Florez
Willy Marcos Valencia
Robert Stempel
Jerry P Palmer
Ashok Balasubramanyam

Publication Date

1-16-2024

Journal

Journal of the Endocrine Society

DOI

10.1210/jendso/bvad179

PMID

38333889

PMCID

PMC10853002

PubMedCentral® Posted Date

2-8-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

islet autoantibodies, epitope-specific autoantibodies, anti-idiotypic antibodies, T cell–mediated autoimmunity, humoral autoimmunity, latent autoimmune diabetes of adults

Abstract

CONTEXT: Autoantibodies directed against the 65-kilodalton isoform of glutamic acid decarboxylase (GAD65Abs) are markers of autoimmune type 1 diabetes (T1D) but are also present in patients with Latent Autoimmune Diabetes of Adults and autoimmune neuromuscular diseases, and also in healthy individuals. Phenotypic differences between these conditions are reflected in epitope-specific GAD65Abs and anti-idiotypic antibodies (anti-Id) against GAD65Abs. We previously reported that 7.8% of T2D patients in the GRADE study have GAD65Abs but found that GAD65Ab positivity was not correlated with beta-cell function, glycated hemoglobin (HbA1c), or fasting glucose levels.

CONTEXT: In this study, we aimed to better characterize islet autoantibodies in this T2D cohort. This is an ancillary study to NCT01794143.

METHODS: We stringently defined GAD65Ab positivity with a competition assay, analyzed GAD65Ab-specific epitopes, and measured GAD65Ab-specific anti-Id in serum.

RESULTS: Competition assays confirmed that 5.9% of the patients were GAD65Ab positive, but beta-cell function was not associated with GAD65Ab positivity, GAD65Ab epitope specificity or GAD65Ab-specific anti-Id. GAD65-related autoantibody responses in GRADE T2D patients resemble profiles in healthy individuals (low GAD65Ab titers, presence of a single autoantibody, lack of a distinct epitope pattern, and presence of anti-Id to diabetes-associated GAD65Ab). In this T2D cohort, GAD65Ab positivity is likely unrelated to the pathogenesis of beta-cell dysfunction.

CONCLUSION: Evidence for islet autoimmunity in the pathophysiology of T2D beta-cell dysfunction is growing, but T1D-associated autoantibodies may not accurately reflect the nature of their autoimmune process.

Comments

This article has been corrected. See J Endocr Soc. 2024 Apr 1;8(5):bvae058.

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