The glutamic acid decarboxylase 65 immunoglobulin G subclass profile differs between adult-onset type 1 diabetes and latent autoimmune diabetes in adults (LADA) up to 3 years after clinical onset

Abstract

Autoantibodies against glutamic acid decarboxylase 65 (GADA) are found frequently in patients with autoimmune diabetes. Immunoglobulin (Ig)G(1) is the most frequent subclass among the GADA IgG subclasses. IgG(4) is a more common subclass in latent autoimmune diabetes in adults (LADA) at clinical onset compared to type 1 diabetes. The aim of this work was to study the different GADA-IgG subclass profiles during a 3-year follow-up in these groups of autoimmune diabetes. Adult-onset subjects, classified as either type 1 (n = 40) or LADA (n = 43), were included in the study. New samples were collected every year from these patients. In addition to conventional GADA analyses, GADA-IgG subclasses were also analysed with a radioimmunoprecipitation assay using biotin-conjugated antibodies (directed against human IgG subclasses and IgM) and streptavidin Sepharose. During 3 years' follow-up, all the IgG subclass levels decreased in type 1 diabetes - IgG(1): P < 0.001; IgG(2): P < 0.001; IgG(3): P < 0.001; IgG(4): P < 0.05 (Friedman's' test) - while levels remained stable for all four subclasses in LADA. GADA IgM, however, decreased in both groups (P < 0.001). Patients with LADA have higher GADA IgG(3) and IgG(4) at clinical onset and seem to maintain the levels and profile of their IgG subclasses up to 3 years after clinical onset, while all the GADA IgG subclass levels decrease in type 1 diabetic patients. This indicates a persistent different immune response in LADA compared to type 1 diabetes and further indicates the difference in pathogenesis.

Fig. 1

Glutamic acid decarboxylase 65 (GADA) antibody levels observed in subjects with type 1 diabetes mellitus (T1DM; n = 40) and latent autoimmune diabetes in adults (LADA) (n = 43). The numbering below the boxes starts with 0 (time of diagnosis) and indicates the number of years after clinical onset. The stars above the boxes indicate the significance of differences in subclass levels between type 1 diabetes and LADA, as given by the Mann–Whitney U-test, *P < 0·05, **P < 0·01 and ***P < 0·001. There appeared to be a decrease in immunoglobulin (Ig)G subclass levels for all subclasses in the group with type 1 diabetes (as indicated by the unbroken lines between the medians) that was not observed in LADA (dotted lines; a–d). The Friedman test indicated a decrease in mean rank for subclass levels in type 1 diabetes: IgG₁ (a, P < 0·001), IgG₂ (b, P < 0·001), IgG₃ (c, P < 0·001) and IgG₄ (d, P = 0·02), but no significant change was observed in LADA. The GADA IgM levels (e) decreased over the years in both type 1 diabetes (P < 0·001) and LADA (P = 0·001). The total GADA was expected to have a similar pattern to that seen in IgG₁. However, the Friedman test did not indicate a statistically significant decrease in total GADA levels for type 1 diabetes (P = 0·07) or LADA (P = 0·11).

Fig. 2

A box-plot of the C-peptide levels in patients with type 1 diabetes mellitus (T1DM) and latent autoimmune diabetes in adults (LADA). Levels of C-peptide were significantly lower in patients with T1DM compared to LADA at clinical onset as well as 3 years after diagnosis. There was also a significant decrease in the LADA group over time, indicated by the Wilcoxon signed rank test (P = 0·03); however, this was not evident in the type 1 diabetes group (P = 0·17).