Autoantibodies to N-terminally truncated GAD improve clinical phenotyping of individuals with adult-onset diabetes: Action LADA 12

Abstract

Aims/hypothesis Adult-onset type 1 diabetes, in which the 65 kDa isoform of GAD (GAD65) is a major autoantigen, has a broad clinical phenotype encompassing variable need for insulin therapy. This study aimed to evaluate whether autoantibodies against N-terminally truncated GAD65 more closely defined a type 1 diabetes phenotype associated with insulin therapy. Methods Of 1114 participants with adult-onset diabetes from the Action LADA (latent autoimmune diabetes in adults) study with sufficient sera, we selected those designated type 1 (n = 511) or type 2 diabetes (n = 603) and retested the samples in radiobinding assays for human full-length GAD65 autoantibodies (f-GADA) and N-terminally truncated (amino acids 96-585) GAD65 autoantibodies (t-GADA). Individuals' clinical phenotypes were analysed according to antibody binding patterns. Results Overall, 478 individuals were f-GADA-positive, 431 were t-GADA-positive and 628 were negative in both assays. Risk of insulin treatment was augmented in t-GADA-positive individuals (OR 4.69 [95% CI 3.57,6.17]) compared with f-GADApositive individuals (OR 3.86 [95% CI 2.95, 5.06]), irrespective of diabetes duration. Of 55 individuals who were f-GADApositive but t-GADA-negative, i.e. with antibody binding restricted to the N-terminus of GAD65, the phenotype was similar to type 2 diabetes with low risk of progression to insulin treatment. Compared with these individuals with N-terminal GAD65-restricted GADA, t-GADA-positive individuals were younger at diagnosis (p = 0.005), leaner (p < 0.0001) and more often had multiple diabetes-associated autoantibodies (28.3% vs 7.3%; p = 0.0005). Conclusions/interpretation In individuals with adult-onset diabetes, presence of N-terminally truncated GAD65 autoantibodies is associated with the clinical phenotype of autoimmune type 1 diabetes and predicts insulin therapy.A list of members of the Action LADA consortium is available in the Appendix.Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-018-4605-3) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Identification of autoimmune type 1 diabetes and multiple organ‐specific autoantibodies in adult‐onset non‐insulin‐requiring diabetes in China: A population‐based multicentre nationwide survey

“…Furthermore, by definition, some patients will have false‐positive autoantibodies, given assay specificities below 100%, but comparison with a large normal control cohort allows us to estimate that the false‐positive rate was likely to be very low. That potential error could be further reduced by the use of novel methods such as electrochemiluminescence assays and autoantibodies to N‐terminally truncated GAD assay. Using assays with high assay specificity in patients in a cohort enriched for the patients with those characteristics to be identified (in the present study, initially non‐insulin‐requiring adult‐onset diabetes), greatly increases the predictive specificity of the assays.…”

Birth and coming of age of islet autoantibodies

“…Low‐affinity antibodies are seen more frequently in individuals who do not have a strong genetic susceptibility to type 1 diabetes and in children who remain positive for only IAA or GADA . The affinities and epitope specificities of IAA and GADA can be used to stratify the progression to type 1 diabetes , and those for GADA can predict insulin therapy in individuals with adult‐onset diabetes . The spread of IA‐2A reactivity against epitopes on the homologous IA‐2β protein is associated with the rapid development of diabetes .…”

Glutamic Acid Decarboxylase Autoantibody Detection by Electrochemiluminescence Assay Identifies Latent Autoimmune Diabetes in Adults with Poor Islet Function

“…However, we also assessed C-peptide concentrations and other clinical indices to evaluate β-cell function in LADA patients, and explored their relationships with ECL-GADA titers. β-Cell function may be associated with the epitope specificity of GADA, according to Achenbach et al [10], who reported that the necessity for insulin therapy could be predicted by the detection of N-terminally-truncated GAD65 autoantibodies in LADA patients. However, the relationship between ECL-GA-DA titer and epitope specificity requires further investigation.…”

“…Furthermore, Krause et al [9] found that GADA affinity varies widely (up to 10,000-fold) in GADA-positive LADA patients, and that it correlates inversely with β-cell function and is strongly associated with the subsequent need for insulin treatment. Additionally, they suggested that the epitope specificity of GADA is associated with the classification of adult-onset diabetes and can be used to predict the requirement for insulin therapy [10]. For example, antibodies against the central or C-terminal domains of glutamic acid decarboxylase 65 (GAD65) tend to be associated with a clinical phenotype of autoimmune T1DM and a need for insulin therapy, whereas antibodies against N-terminal epitopes tend to be associated with a similar clinical phenotype to T2DM and a lack of requirement for insulin.…”