We read with great interest the article by Liu et al. (1) demonstrating that progression of diabetes among subjects with latent autoimmune diabetes in adults (LADA) having low titer of GAD antibody (GADA) is similar to that in subjects with type 2 diabetes over the period of 3 years. This is a large population-based, prospective, well-controlled study with well-characterized subjects.
Major epidemiologic studies such as Diabetes Autoimmunity Study in the Young (DAISY), TrialNet Pathway to Prevention Study, and The Environmental Determinants of Diabetes in the Young (TEDDY) showed that 30–60% of autoantibody positivity is atttributable to a single islet autoantibody with majority of these being either GADA or insulin antibody (IAA). Patients who express only a single islet autoantibody are at low risk for developing type 1 diabetes compared with those with multiple autoantibodies. Relatives expressing only IAA in the DPT-1 (Diabetes Prevention Trial–Type 1) study essentially did not progress to diabetes (2). Similarly, Maruyama et al. (3) have also reported that patients with high GADA titers had shorter disease durations and lower serum C-peptide levels than patients with low-titer GADA and GADA-negative type 2 diabetes.
All these studies, including the study by Liu et al., have estimated GADA by radioimmunoassay, which is the gold-standard assay at present. However, our group has shown that low-titer GADA is mainly low affinity and does not predict the progression of diabetes (4–6). Furthermore, our group previously developed electrochemiluminescence (ECL)-based GADA and IAA assays that were more specific than radioimmunoassay. The ECL-GADA and -IAA assays were able to detect disease-relevant, high-affinity autoantibodies while ignoring a low-affinity signal that did not predict the development of multiple islet autoantibodies and progression to diabetes. We also hypothesized that most of these single antibodies may result from immunization with a cross-reactive molecule, whereas higher-affinity IAA or GADA result from immunization with an islet autoantigen itself (4–6).
Considering our previous research findings, we feel that the low titer of GADA found in the study by Liu et al. (1) might be low-affinity antibodies representing biologically false positivity. That may be the reason for similar disease progression in individuals with low-titer GADA compared with type 2 diabetes in their study.
It will be interesting to analyze GADA affinity and also GADA profile by ECL-based assay to differentiate false-positive antibody from true-positive antibodies. This information will provide an insight on disease progression in relation with GADA affinity.
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Duality of Interest. No potential conflicts of interest relevant to this article were reported.
