{"doi":"10.1016/j.chembiol.2022.08.001","title":"In vivo drug discovery for increasing incretin-expressing cells identifies DYRK inhibitors that reinforce the enteroendocrine system","abstract":"Analogs of the incretin hormones Gip and Glp-1 are used to treat type 2 diabetes and obesity. Findings in experimental models suggest that manipulating several hormones simultaneously may be more effective. To identify small molecules that increase the number of incretin-expressing cells, we established a high-throughput in vivo chemical screen by using the gip promoter to drive the expression of luciferase in zebrafish. All hits increased the numbers of neurogenin 3-expressing enteroendocrine progenitors, Gip-expressing K-cells, and Glp-1-expressing L-cells. One of the hits, a dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) inhibitor, additionally decreased glucose levels in both larval and juvenile fish. Knock-down experiments indicated that nfatc4, a downstream mediator of DYRKs, regulates incretin+ cell number in zebrafish, and that Dyrk1b regulates Glp-1 expression in an enteroendocrine cell line. DYRK inhibition also increased the number of incretin-expressing cells in diabetic mice, suggesting a conserved reinforcement of the enteroendocrine system, with possible implications for diabetes.","journal":"Cell chemical biology","year":2022,"id":261220,"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":15,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9545,"is_data_producer":false,"deposit_databanks":null,"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":915490,"name":"Michishige Terasaki","orcid":"0000-0002-7405-7419","position":1,"is_corresponding":false},{"id":916048,"name":"Charlotte L. Mattsson","orcid":null,"position":2,"is_corresponding":false},{"id":915491,"name":"Romain Teinturier","orcid":"0000-0001-9430-9508","position":3,"is_corresponding":false},{"id":915492,"name":"Jérémie Charbord","orcid":"0000-0002-8411-8182","position":4,"is_corresponding":false},{"id":269958,"name":"Ercument Dirice","orcid":"0000-0003-2792-7204","position":5,"is_corresponding":false},{"id":915493,"name":"Ka‐Cheuk Liu","orcid":"0000-0001-6082-8801","position":6,"is_corresponding":false},{"id":915494,"name":"Michael G. Miskelly","orcid":"0000-0002-4688-5719","position":7,"is_corresponding":false},{"id":237947,"name":"Qiao Zhou","orcid":"0000-0002-0099-3909","position":8,"is_corresponding":false},{"id":915495,"name":"Nils Wierup","orcid":"0000-0001-6824-4093","position":9,"is_corresponding":false},{"id":269959,"name":"Rohit Kulkarni","orcid":"0000-0001-5029-6119","position":10,"is_corresponding":false},{"id":789975,"name":"Olov Andersson","orcid":"0000-0001-6715-781X","position":11,"is_corresponding":false},{"id":916047,"name":"Lianhe Chu","orcid":null,"position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":null,"created_at":"2026-07-19T00:26:12.158801Z","pmid":"35998625","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":[]}