Identification of Autoantibodies to a Hybrid Insulin Peptide in Type 1 Diabetes

Abstract

Type 1 diabetes (T1D) is a chronic autoimmune disease that attacks the insulin-producing b cells of the pancreatic islets. Autoantibodies to b cell proteins typically appear in the circulation years before disease onset, and serve as the most accurate biomarkers of T1D risk. Our laboratory has recently discovered novel b cell proteins comprising hybrid proinsulin:islet amyloid polypeptide peptides (IAPP). T cells from a diabetic mouse model and T1D patients are activated by these hybrid peptides. In this study, we asked whether these hybrid molecules could serve as antigens for autoantibodies in T1D and prediabetic patients. We analyzed sera from T1D patients, prediabetics and healthy age-matched donors. Using a highly sensitive electrochemiluminescence assay, sera were screened for binding to recombinant proinsulin:IAPP probes or truncated derivatives. Our results show that sera from T1D patients contain antibodies that bind larger hybrid proinsulin:IAPP probes, but not proinsulin or insulin, at significantly increased frequencies compared to normal donors. Examination of sera from prediabetic patients confirms titers of antibodies to these hybrid probes in more than 80% of individuals, often before seroconversion. These results suggest that hybrid insulin peptides are common autoantigens in T1D and prediabetic patients, and that antibodies to these peptides may serve as valuable early biomarkers of the disease.

Immunological and virological triggers of type 1 diabetes: insights and implications

“…Insulin autoantibodies are frequently the first to emerge in young children, followed sequentially by any of the others (islet antigen 2 (IA-2), glutamic acid decarboxylase 65 (GAD-65) and zinc transporter 8 (ZnT8). At clinical onset, 95% of patients have antibodies to at least one of these beta cell proteins ( 11 ). Several factors play a part in determining the susceptibility of an individual towards the loss of immunologic self-tolerance, including age, sex, genetics, and specific environmental exposure.…”