Yang, Mei-LingConnolly, Sean E.Gee, Renelle J.Lam, TuKiet T.Kanyo, JeanPeng, JianGuyer, PerrinSyed, FarooqTse, Hubert M.Clarke, Steven G.Clarke, Catherine F.James, Eddie A.Speake, CateEvans-Molina, CarmellaArvan, PeterHerold, Kevan C.Wen, LiMamula, Mark J2024-03-152024-03-152022Yang ML, Connolly SE, Gee RJ, et al. Carbonyl Posttranslational Modification Associated With Early-Onset Type 1 Diabetes Autoimmunity. Diabetes. 2022;71(9):1979-1993. doi:10.2337/db21-0989https://hdl.handle.net/1805/39258Inflammation and oxidative stress in pancreatic islets amplify the appearance of various posttranslational modifications to self-proteins. In this study, we identified a select group of carbonylated islet proteins arising before the onset of hyperglycemia in NOD mice. Of interest, we identified carbonyl modification of the prolyl-4-hydroxylase β subunit (P4Hb) that is responsible for proinsulin folding and trafficking as an autoantigen in both human and murine type 1 diabetes. We found that carbonylated P4Hb is amplified in stressed islets coincident with decreased glucose-stimulated insulin secretion and altered proinsulin-to-insulin ratios. Autoantibodies against P4Hb were detected in prediabetic NOD mice and in early human type 1 diabetes prior to the onset of anti-insulin autoimmunity. Moreover, we identify autoreactive CD4+ T-cell responses toward carbonyl-P4Hb epitopes in the circulation of patients with type 1 diabetes. Our studies provide mechanistic insight into the pathways of proinsulin metabolism and in creating autoantigenic forms of insulin in type 1 diabetes.en-USPublisher PolicyType 1 diabetes mellitusInsulinAutoantigensProteinsArticle