DPD epitope-specific glutamic acid decarboxylase GAD)65 autoantibodies in children with Type 1 diabetes

Authors: BANSAL, N - Baylor College Of Medicine; HAMPE, C - University Of Washington; RODRIGUEZ, L - Baylor College Of Medicine; O'BRIAN, SMITH - Children'S Nutrition Research Center (CNRC); KUSHNER, J - Baylor College Of Medicine; BALASUBRAMANYAM, A - Baylor College Of Medicine; REDONDO, M - Baylor College Of Medicine

Submitted to: Diabetic Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/19/2016
Publication Date: 5/1/2017
Citation: Bansal, N., Hampe, C.S., Rodriguez, L., O'Brian, S.E., Kushner, J., Balasubramanyam, A., Redondo, M.J. 2017. DPD epitope-specific glutamic acid decarboxylase (GAD)65 autoantibodies in children with Type 1 diabetes. Diabetic Medicine. 34(5):641-646.

Interpretive Summary: Type 1 diabetes (T1D) is a heterogeneous disease in its clinical presentation, which suggests differences in its causes and mechanisms of disease. Islet autoantibodies are markers of the autoimmune attack on the insulin producing pancreatic beta-cells. Among them, GAD65 autoantibodies are present in about 60% of the individuals with new onset T1D. A specific type of GAD65 autoantibodies, termed DPD epitope-specific GAD65 autoaantibodies, has been previously reported in adults with a slowly progressive form of autoimmune diabetes termed Latent Autoimmune Diabetes in Adults (LADA). Individuals with LADA have autoimmune diabetes that presents in adulthood with a very slowly progressive and mild disease, as opposed to the rapid course that is usually seen in children. We hypothesized that children with DPD epitope-specific GAD 65 autoantibodies will have characteristics of a milder form of T1D. We found that children with new onset T1D with DPD epitope specific GAD65 autoantibodies had better diabetes control. This study supports the concept that the clinical heterogeneity of T1D has an immunological basis. This is important as clinical trials that use immunomodulatory treatments to prevent T1D may need to be tailored to the specific immunologic patient characteristcs.

Technical Abstract: To study whether DPD epitope-specific glutamate decarboxylase autoantibodies are found more frequently in children with milder forms of Type 1 diabetes. We prospectively evaluated 75 children with new-onset autoimmune Type 1 diabetes, in whom we collected demographic, anthropometric and clinical data and measured islet autoantibodies. Glutamate decarboxylase 65 autoantibody-positive samples were analysed for epitope specificities using recombinant Fab against the DPD-defined epitope of glutamate decarboxylase 65. After adjustment for age, positive DPD epitope recognition was significantly associated with higher C-peptide levels at onset (P = 0.02, r2 =0.21, n = 35), and high DPD recognition in the highest quartile tended to be associated with HbA1c <= 53 mmol/mol (7%) at the last follow-up [mean (sd) follow-up 1.3 (0.4) years; P = 0.07; for the model, P = 0.044, n = 30)]. Age- and sex-adjusted BMI percentile was significantly correlated with recognition of the DPD-defined epitope (P < 0.03, r2 =0.14, n = 34), but this correlation was driven by the older age group (age >= 10 years; P = 0.016, r2 =0.27, n = 21) and was not significant in younger children (P = 0.93, n = 13). There were no independent associations with sex, race/ethnicity, diabetic ketoacidosis, HbA1c , HLA DR3-DQ2/DR4-DQ8 or autoantibody number. Our findings suggest that recognition of the DPD-defined glutamate decarboxylase 65 autoantibody epitope at Type 1 diabetes onset is directly associated with beta-cell function, BMI and age, which supports the hypothesis that immunological factors contribute to the clinical heterogeneity of Type 1 diabetes. Larger studies relating epitope-specific glutamate decarboxylase 65 autoantibody to clinical phenotype in children with Type 1 diabetes are warranted.