{"doi":"10.1101/2021.04.28.441829","title":"Citrullination of glucokinase linked to autoimmune diabetes","abstract":"Abstract Inflammation, including reactive oxygen species and inflammatory cytokines in tissue microenvironments amplify the appearance of various post-translational modifications (PTMs) of self-proteins. Previously, a number of PTMs have been identified as autoimmune biomarkers in the initiation and progression of Type 1 diabetes (T1D). Herein, we have identified the citrullination of glucokinase (GK) as a result of inflammation, triggering autoimmunity and affecting its biological functions. Glucokinase is predominantly expressed in hepatocytes to regulate glycogen synthesis, and in pancreatic beta cells, where it acts as a glucose sensor to initiate glycolysis and insulin signaling. Herein, we demonstrate that glucokinase is citrullinated in inflamed non-obese diabetic (NOD) islets as well as in human GK. Autoantibodies against both native and citrullinated GK arise in both spontaneous human T1D and murine models. Likewise, autoreactive CD4 + T cells to both native and citrullinated glucokinase epitopes are present in the circulation of T1D patients. Finally, citrullination alters GK biologic activity and suppresses glucose-stimulated insulin secretion. Our studies define glucokinase as a T1D biomarker, providing new insights into altering glucose metabolism, creating neoautoantigens, and better define the broad impact of PTMs on the tissue pathology of T1D.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":224082,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.956,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":826144,"name":"Sheryl Horstman","orcid":null,"position":1,"is_corresponding":false},{"id":821097,"name":"Renelle J. Gee","orcid":null,"position":2,"is_corresponding":false},{"id":357605,"name":"Perrin Guyer","orcid":null,"position":3,"is_corresponding":false},{"id":271366,"name":"TuKiet T. Lam","orcid":"0000-0002-4850-3462","position":4,"is_corresponding":false},{"id":64846,"name":"Jean Kanyo","orcid":"0000-0003-4814-7573","position":5,"is_corresponding":false},{"id":571209,"name":"Ana Luisa Perdigoto","orcid":"0000-0002-0348-9329","position":6,"is_corresponding":false},{"id":271012,"name":"Cate Speake","orcid":"0000-0003-1480-4272","position":7,"is_corresponding":false},{"id":71415,"name":"Carla J. Greenbaum","orcid":"0000-0003-4451-9800","position":8,"is_corresponding":false},{"id":457127,"name":"Lut Overbergh","orcid":"0000-0001-7126-356X","position":9,"is_corresponding":false},{"id":254925,"name":"Richard G. Kibbey","orcid":"0000-0001-6768-3473","position":10,"is_corresponding":false},{"id":230352,"name":"Kevan C. Herold","orcid":"0000-0003-1534-6613","position":11,"is_corresponding":false},{"id":108429,"name":"Eddie A. James","orcid":"0000-0002-7217-5729","position":12,"is_corresponding":false},{"id":649480,"name":"Mark J. Mamula","orcid":"0000-0003-4822-2908","position":13,"is_corresponding":false},{"id":815432,"name":"Mei-Ling Yang","orcid":"0000-0003-1687-2463","position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":null,"created_at":"2026-07-18T23:54:14.760456Z","pmid":null,"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":[]}