{"doi":"10.2337/db21-0989","title":"Carbonyl Posttranslational Modification Associated With Early-Onset Type 1 Diabetes Autoimmunity","abstract":"Inflammation 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.","journal":"Diabetes","year":2022,"id":251247,"datarank":0.7164001200817786,"base_score":3.258096538021482,"endowment":3.258096538021482,"self_citation_contribution":0.4887144807032224,"citation_network_contribution":0.22768563937855615,"self_endowment_contribution":0.4887144807032224,"citer_contribution":0.22768563937855615,"corpus_percentile":null,"corpus_rank":null,"citation_count":25,"citer_count":16,"citers_with_citation_signal":16,"citers_with_endowment":16,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9551,"is_data_producer":true,"deposit_databanks":{"figshare":["10.2337/figshare.20103134"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":820749,"name":"Seán Connolly","orcid":"0000-0003-4884-861X","position":1,"is_corresponding":false},{"id":821097,"name":"Renelle J. Gee","orcid":null,"position":2,"is_corresponding":false},{"id":271366,"name":"TuKiet T. Lam","orcid":"0000-0002-4850-3462","position":3,"is_corresponding":false},{"id":64846,"name":"Jean Kanyo","orcid":"0000-0003-4814-7573","position":4,"is_corresponding":false},{"id":894077,"name":"Jian Peng","orcid":"0000-0003-0332-0248","position":5,"is_corresponding":false},{"id":357605,"name":"Perrin Guyer","orcid":null,"position":6,"is_corresponding":false},{"id":251261,"name":"Farooq Syed","orcid":"0000-0002-0284-0631","position":7,"is_corresponding":false},{"id":625374,"name":"Hubert M. Tse","orcid":"0000-0001-5861-7597","position":8,"is_corresponding":false},{"id":820750,"name":"Steven Clarke","orcid":"0000-0002-7303-6632","position":9,"is_corresponding":false},{"id":317472,"name":"Catherine F. Clarke","orcid":"0000-0002-6426-3833","position":10,"is_corresponding":false},{"id":108429,"name":"Eddie A. James","orcid":"0000-0002-7217-5729","position":11,"is_corresponding":false},{"id":271012,"name":"Cate Speake","orcid":"0000-0003-1480-4272","position":12,"is_corresponding":false},{"id":7388,"name":"Carmella Evans‐Molina","orcid":"0000-0001-7764-8663","position":13,"is_corresponding":false},{"id":33730,"name":"Peter Arvan","orcid":"0000-0002-4007-8799","position":14,"is_corresponding":false},{"id":230352,"name":"Kevan C. Herold","orcid":"0000-0003-1534-6613","position":15,"is_corresponding":false},{"id":307520,"name":"Wen Li","orcid":"0000-0002-8805-2934","position":16,"is_corresponding":false},{"id":649480,"name":"Mark J. Mamula","orcid":"0000-0003-4822-2908","position":17,"is_corresponding":false},{"id":815432,"name":"Mei-Ling Yang","orcid":"0000-0003-1687-2463","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-19T00:24:37.429628Z","pmid":"35730902","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}