Islet Autoantibody Level Distribution in Type 1 Diabetes and Their Association With Genetic and Clinical Characteristics

Abstract

Context The importance of the autoantibody level at diagnosis of type 1 diabetes is not clear. Objective We aimed to assess the association of glutamate decarboxylase (GADA), islet antigen-2 (IA-2A) and zinc transporter 8 (ZnT8A) autoantibody levels with clinical and genetic characteristics at diagnosis of type 1 diabetes. Design, Setting and Patients We conducted a prospective cross-sectional study. GADA, IA-2A and ZnT8A were measured in 1644 individuals with type 1 diabetes at diagnosis using radiobinding assays. Associations between autoantibody levels and the clinical and genetic characteristics for individuals were assessed in those positive for these autoantibodies. We performed replication in independent cohort of 449 people with type 1 diabetes Results GADA and IA-2A levels exhibited a bimodal distribution at diagnosis. High GADA level was associated with older age at diagnosis (median 27 years vs. 19 years, P = 9 × 10−17), female sex (52% vs. 37%, P = 1 × 10−8), other autoimmune diseases (13% vs. 6%, P = 3 × 10−6) and HLA-DR3-DQ2 (58% vs. 51%, P = 0.006). High IA-2A level was associated with younger age of diagnosis (median 17 years vs. 23 years, P = 3 × 10−7), HLA-DR4-DQ8 (66% vs. 50%, P = 1 × 10−6) and ZnT8A positivity (77% vs. 52%, P = 1 × 10−15). We replicated our findings in an independent cohort of 449 people with type 1 diabetes where autoantibodies were measured using enzyme-linked immunosorbent assays (ELISA). Conclusions Islet autoantibody levels provide additional information over positivity in type 1 diabetes at diagnosis. Bimodality of GADA and IA-2A autoantibody levels highlights the novel aspect of heterogeneity of type 1 diabetes. This may have implications on type 1 diabetes prediction, treatment and pathogenesis.

The importance of biomarker development for monitoring type 1 diabetes progression rate and therapeutic responsiveness

“…While islet autoantibodies are crucial to identify individuals “at-risk” of T1D for trials to prevent or delay the onset of the condition, few data suggest that they represent useful biomarkers to monitor efficacy in the way that models of beta cell function, including C-peptide and immune cell compartments, can be used ( 48 – 51 ). Firstly, some tests use a positive/negative readout for islet autoantibodies and only recently has there been a focus on the potential usefulness of islet autoantibody level in studies of type 1 diabetes ( 52 , 53 ). However interestingly, in a TrialNet study blocking the CD28/CD80/CD86 costimulatory axis with CTLA4Ig (Abatacept) in individuals with diabetes, participants with a poor response (resistance: measured by modeling rate of decline of C peptide) had a transient increase in activated B cell reprogrammed costimulatory ligand gene expression, and reduced inhibition of anti-insulin antibodies ( 54 ).…”

The challenges of identifying and studying type 1 diabetes in adults

“…A consistent finding across studies, irrespective of type 1 diabetes definition, is that when autoantibodies are present, autoantibody patterns vary with onset age. In children, multi-autoantibody-positive type 1 diabetes cases are more common than in adults [ 35 , 36 , 42 , 43 ] and IA-2A positivity is more frequent. Moreover, a higher IA-2A titre is associated with earlier type 1 diabetes onset.…”

“…Moreover, a higher IA-2A titre is associated with earlier type 1 diabetes onset. Conversely, in adults, GADA is the predominant autoantibody, irrespective of ethnicity [ 13 , 32 , 35 , 36 , 43 ]. Islet autoantibodies are more persistent after diagnosis in adults than in children, which may reflect the greater prevalence of GADA and/or retained antigenic stimulus [ 44 ].…”