Abstract 20: Pattern of islet antibodies and their persistence among type 1 diabetes patients from North India

Background: Autoantibodies to glutamate acid decarboxylase (GAD65), insulinoma-associated antigen 2 (IA-2), and Zinc transporter 8 (ZnT8), are frequently used in the evaluation of the autoimmune response among subjects with youth onset diabetes. Temporal patterns of antibody levels may vary according to the type of antibody with inter-individual differences. The major determinants of T1DM genetic susceptibility are HLA DR and DQ molecules. Recently, ultrasensitive C-peptide assays have demonstrated that the majority of people with T1DM have residual C-peptide “micro-secretion”, suggesting that some beta cells have escaped immune attack or regenerated. Objectives: 1. To determine the prevalence of islet autoimmunity, which includes GAD65, IA2 and ZnT8 antibodypositivity, at varying time points since the diagnosis. 2. To study median survival time of various islet autoantibodies and Fasting C-peptide (FCP) levels. 3. To determine association of HLA genotype with islet antibody positivity as well as antibodysurvival. 4. To evaluate differences in clinical and biochemical profile of subjects with islet antibody positiveand negative T1DM. Methods: The natural course of islet cell antibodies and C-peptide levels was assessed at intervals of 2-5 yrs, 5-10 yrs and & >10 years from the baseline. Persistence of islet antibody and C-peptide secretion was tested in participants who had antibody positivity or detectable C-peptide levels in their initial sample. Islet antibodies were measured using commercially available ELISA kits (RSR Ltd, UK), while C-peptide was measured using electrochemiluminescence immunoassay (Roche Diagnostics, Germany). HLA typing was performed using Lab Type PCR-SSO ® (sequence-specific oligonucleotides) kits (One Lambda, Inc, USA). HLA allele assignment was performed through HLA Fusion software. Results: At baseline, we evaluated a total of 366 participants with clinical T1DM and a median diabetes duration of 6 years. Overall positivity was 67% for any of three antibodies tested, which increased to 76% in subset of patients (n = 125) with diabetes duration of <2 years. In the persistence analysis, we observed that autoreactivity to ZnT8 and IA2 declined earlier compared to GAD65Ab, which remained stable even after 10 years of follow-up (median survival times: 7 years, 6 years and 15 years, respectively). Fasting C-peptide had a significantly shorter survival in islet antibody positive versus negative group (4 years versus 7 years, p <0.01). 72% of T1DM patients in our cohort were HLA-DRB1*03 positive, while only 8.2% were positive for HLA-DRB1*04. HLA-DRB1*03 allele was observed to be significantly associated with presence of GAD antibodies while HLA-DRB1*04 allele was observed to be significantly associated with ZnT8 antibody positivity. We did not observe any association of HLA-DRB1 status with antibody persistence. No statistically significant difference was observed between antibody positive and negative individuals in any of the clinical and biochemical parameters except for positivity for tissue transglutaminase antibody and FCP survival.