{"doi":"10.1016/j.celrep.2024.115057","title":"Pancreatic β cell interleukin-22 receptor subunit alpha 1 deficiency impairs β cell function in type 2 diabetes via cytochrome b5 reductase 3","abstract":"Impaired β cell function is a hallmark of type 2 diabetes (T2D), but the underlying cellular signaling machineries that regulate β cell function remain unknown. Here, we identify that the interleukin-22 receptor subunit alpha 1 (IL-22RA1), known as a co-receptor for IL-22, is downregulated in human and mouse T2D β cells. Mice with β cell Il22ra1 knockout (Il22ra1βKO) exhibit defective insulin secretion and impaired glucose tolerance after being fed a high-fat diet (HFD) or an HFD/low dose of streptozotocin (STZ). Mechanistically, β cell IL-22RA1 deficiency inhibits cytochrome b5 reductase 3 (CYB5R3) expression via the IL-22RA1/signal transducer and activator of the transcription 3 (STAT3)/c-Jun axis, thereby impairing mitochondrial function and reducing β cell identity. Overexpression of CYB5R3 reinstates mitochondrial function, β cell identity, and insulin secretion in Il22ra1βKO mice. Moreover, the pharmacological activation of CYB5R3 with tetrahydroindenoindole restores insulin secretion in Il22ra1βKO mice, IL-22RA1-knockdown human islets, and Min6 cells. In conclusion, these findings suggest an important role of IL-22RA1 in preserving β cell function in T2D, which offers a potential therapeutic target for treating diabetes.","journal":"Cell Reports","year":2024,"id":448060,"datarank":0.31924470960965673,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"self_citation_contribution":0.29188652235829704,"citation_network_contribution":0.027358187251359693,"self_endowment_contribution":0.29188652235829704,"citer_contribution":0.027358187251359693,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":5,"citers_with_citation_signal":2,"citers_with_endowment":2,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9557,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE281651","GSE281652"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1266699,"name":"Shuting Xie","orcid":"0000-0003-4550-2568","position":1,"is_corresponding":false},{"id":1266700,"name":"Tongyu Wang","orcid":"0009-0008-6618-3088","position":2,"is_corresponding":false},{"id":1267113,"name":"Yeping Huang","orcid":null,"position":3,"is_corresponding":false},{"id":527496,"name":"Hong Zhang","orcid":"0000-0002-6417-8399","position":4,"is_corresponding":false},{"id":1266701,"name":"Danfeng Peng","orcid":"0000-0003-0014-8817","position":5,"is_corresponding":false},{"id":1266702,"name":"Yifan Feng","orcid":"0000-0002-4291-6493","position":6,"is_corresponding":false},{"id":1267114,"name":"Yumei Yang","orcid":null,"position":7,"is_corresponding":false},{"id":1266703,"name":"Zheyu Zhang","orcid":"0000-0003-1907-0765","position":8,"is_corresponding":false},{"id":1266704,"name":"Yunxia Zhu","orcid":"0000-0002-8695-7545","position":9,"is_corresponding":false},{"id":486072,"name":"Zhuo‐Xian Meng","orcid":"0000-0001-8177-5593","position":10,"is_corresponding":false},{"id":1266705,"name":"Rong Zhang","orcid":"0000-0002-0003-2200","position":11,"is_corresponding":false},{"id":1266706,"name":"Xiaomu Li","orcid":"0000-0001-8337-0207","position":12,"is_corresponding":false},{"id":1266707,"name":"Hao Yin","orcid":"0000-0002-0018-3228","position":13,"is_corresponding":false},{"id":1266708,"name":"Jie Yu","orcid":"0000-0002-4796-7177","position":14,"is_corresponding":false},{"id":90065,"name":"Cheng Hu","orcid":"0000-0003-4314-2386","position":15,"is_corresponding":false},{"id":1266698,"name":"Yu Fan","orcid":"0000-0003-4288-2999","position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":null,"created_at":"2026-07-19T02:02:08.018689Z","pmid":"39675006","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":[]}