Improving clinical utility of GAD65 autoantibodies by electrochemiluminescence assay and clinical phenotype when identifying autoimmune adult-onset diabetes

Yong Gu ,Marian Rewers ,Samuel T Jerram ,Xiaofan Jia ,Jean M Lawrence ,Dongmei Miao ,Liping Yu ,Assiamira Ferrara ,Tanwi Vartak ,Fran Dong ,Richard Leslie

doi:10.1007/s00125-021-05492-6

Abstract

Aims/hypothesisIt is important to differentiate the two major phenotypes of adult-onset diabetes, autoimmune type 1 diabetes and non-autoimmune type 2 diabetes, especially as type 1 diabetes presents in adulthood. Serum GAD65 autoantibodies (GADA) are the most sensitive biomarker for adult-onset autoimmune type 1 diabetes, but the clinical value of GADA by current standard radiobinding assays (RBA) remains questionable. The present study focused on the clinical utility of GADA differentiated by a new electrochemiluminescence (ECL) assay in patients with adult-onset diabetes.MethodsTwo cohorts were analysed including 771 diabetic participants, 30–70 years old, from the Action LADA study (n = 6156), and 2063 diabetic participants, 20–45 years old, from the Diabetes in Young Adults (DiYA) study. Clinical characteristics of participants, including requirement of early insulin treatment, BMI and development of multiple islet autoantibodies, were analysed according to the status of RBA-GADA and ECL-GADA, respectively, and compared between these two assays.ResultsGADA was the most prevalent and predominant autoantibody, >90% in both cohorts. GADA positivity by either RBA or ECL assay significantly discriminated clinical type 1 from type 2 diabetes. However, in both cohorts, participants with ECL-GADA positivity were more likely to require early insulin treatment, have multiple islet autoantibodies, and be less overweight (for all p < 0.0001). However, clinical phenotype, age at diagnosis and BMI independently improved positive predictive value (PPV) for the requirement of insulin treatment, even augmenting ECL-GADA. Participants with GADA detectable by RBA, but not confirmed by ECL, had a phenotype more similar to type 2 diabetes. These RBA-GADA positive individuals had lower affinity GADA compared with participants in which GADA was confirmed by ECL assay.Conclusions/interpretationDetection of GADA by ECL assay, given technical advantages over RBA-GADA, identified adult-onset diabetes patients at higher risk of requiring early insulin treatment, as did clinical phenotype, together allowing for more accurate clinical diagnosis and management.Graphical abstract

Highlights

GAD65 autoantibody (GADA) positive participants have either biologically false positive GADA or GADA of limited clinical utility
In adult-onset autoimmune diabetes GADA is dominant Two distinct cohorts covering a wide age range of recently diagnosed adult-onset diabetes patients (Action latent autoimmune diabetes in adults (LADA) and Diabetes in Young Adults (DiYA)) were studied using two different radiobinding assays (RBA)-GADA assays, as well as assays for IA-2A or zinc transporter-8 autoantibodies (ZnT8A), in their respective centralised laboratories, while the same ECL- GADA assay was used for both cohorts in one centralised laboratory
The overall islet autoantibodies (IAbs) positivity, including GADA, IA-2A and ZnT8A is summarised in Fig. 2 for both the Action LADA (Fig. 2a) and the DiYA studies (Fig. 2b)

Summary

Introduction

GADA positive participants have either biologically false positive GADA or GADA of limited clinical utility. Our recently developed electrochemiluminescence (ECL) assay for GADA was more predictive of progression to type 1 diabetes than current radiobinding assays (RBA) in several major clinical trials [6, 7]. The present study aims to evaluate, for the first time, GADA by ECL assay, compared with the standard RBA, in individuals with adult-onset diabetes. We hypothesised that identification of GADA using the ECL assay, compared with the RBA, would have greater clinical utility in screening adult-onset autoimmune diabetes by allowing for more accurate clinical diagnosis to the benefit of clinical care. Distinguishing adult-onset type 1 diabetes from type 2 diabetes is clinically important and commonly employs the GAD65 autoantibody (GADA) assay [5]. Since GADA is the dominant, often the only, diabetes-associated autoantibody in adult-onset diabetes, it is possible that some

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