期刊
DIABETOLOGIA
卷 58, 期 12, 页码 2851-2860出版社
SPRINGER
DOI: 10.1007/s00125-015-3746-x
关键词
Insulin autoantibodies; Oxidative stress; Post-translational modification; Reactive oxygen species; Type 1 diabetes
资金
- EFSD Albert Renold Fellowship
- Fondazione Livio Patrizi SIMI award
- University Campus Bio-Medico
- Queen Mary University
- Ministero della Salute, Giovani Ricercatori [2009-1607545]
- Ministero Universita e Ricerca Scientifica, Progetti di Interesse Nazionale PRIN
Aim/hypothesis Insulin is the most specific beta cell antigen and a potential primary autoantigen in type 1 diabetes. Insulin autoantibodies (IAAs) are the earliest marker of beta cell autoimmunity; however, only slightly more than 50% of children and even fewer adults newly diagnosed with type 1 diabetes are IAA positive. The aim of this investigation was to determine if oxidative post-translational modification (oxPTM) of insulin by reactive oxidants associated with islet inflammation generates neoepitopes that stimulate an immune response in individuals with type 1 diabetes. Methods oxPTM of insulin was generated using ribose and various reactive oxygen species. Modifications were analysed by SDS-PAGE, three-dimensional fluorescence and MS. Autoreactivity to oxPTM insulin (oxPTM-INS) was observed by ELISA and western blotting, using sera from participants with type 1 or type 2 diabetes and healthy controls as probes. IAA was measured using the gold-standard radiobinding assay (RBA). Results MS of oxPTM-INS identified chlorination of Tyr16 and Tyr26; oxidation of His5, Cys7 and Phe24; and glycation of Lys29 and Phe1 in chain B. Significantly higher binding to oxPTM-INS vs native insulin was observed in participants with type 1 diabetes, with 84% sensitivity compared with 61% sensitivity for RBA. oxPTM-INS autoantibodies and IAA co-existed in 50% of those with type 1 diabetes. Importantly 34% of those with diabetes who were IAA negative were oxPTM-INS positive. Altogether, 95% of participants with type 1 diabetes presented with autoimmunity to insulin by RBA, oxPTM-INS or both. Binding to oxPTM-INS was directed towards oxPTM-INS fragments with slower mobility than native insulin. Conclusion/interpetation These data suggest that oxPTM-INS is a potential autoantigen in individuals with new-onset type 1 diabetes.
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