학술논문
GAD65Abs Are Not Associated With Beta-Cell Dysfunction in Patients With T2D in the GRADE Study
Clinical Research Article
Clinical Research Article
Document Type
Clinical report
Author
Hampe, Christiane S.; Shojaie, Ali; Brooks-Worrell, Barbara; Dibay, Sepideh; Utzschneider, Kristina; Kahn, Steven E.; Larkin, Mary E.; Johnson, Mary L.; Younes, Naji; Rasouli, Neda; Desouza, Cyrus; Cohen, Robert M.; Park, Jean Y.; Florez, Hermes J.; Valencia, Willy Marcos; Stempel, Robert; Palmer, Jerry P.; Balasubramanyam, Ashok
Source
Journal of the Endocrine Society. March 2024, Vol. 8 Issue 3
Subject
Language
English
ISSN
2472-1972
Abstract
Beta-cell dysfunction is critical to the pathophysiology of all forms of diabetes [1-6]. Whereas islet autoimmunity is considered the predominant cause of beta-cell dysfunction in patients with type 1 diabetes [...]
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-idiotype 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. Key Words: islet autoantibodies, epitope-specific autoantibodies, anti-idiotypic antibodies, T cell-mediated autoimmunity, humoral autoimmunity, latent autoimmune diabetes of adults Abbreviations: anti-Id, anti-idiotypic antibodies; GAD65, glutamic acid decarboxylase 65-kilodalton isoform; GAD65Abs, GAD65 autoantibodies; GRADE, Glycemia Reduction Approaches in Diabetes--a Comparative Effectiveness; HbA1c, glycated hemoglobin; HOMA2-S, Homeostasis Model Assessment of steady-state insulin sensitivity; LADA, latent autoimmune diabetes of adults; OGTT, oral glucose tolerance test; T1D, type 1 diabetes; T2D, type 2 diabetes.
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-idiotype 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. Key Words: islet autoantibodies, epitope-specific autoantibodies, anti-idiotypic antibodies, T cell-mediated autoimmunity, humoral autoimmunity, latent autoimmune diabetes of adults Abbreviations: anti-Id, anti-idiotypic antibodies; GAD65, glutamic acid decarboxylase 65-kilodalton isoform; GAD65Abs, GAD65 autoantibodies; GRADE, Glycemia Reduction Approaches in Diabetes--a Comparative Effectiveness; HbA1c, glycated hemoglobin; HOMA2-S, Homeostasis Model Assessment of steady-state insulin sensitivity; LADA, latent autoimmune diabetes of adults; OGTT, oral glucose tolerance test; T1D, type 1 diabetes; T2D, type 2 diabetes.