{"doi":"10.1016/j.molmet.2025.102134","title":"C3aR1 on β cells enhances β cell function and survival to maintain glucose homeostasis","abstract":"OBJECTIVE: Pancreatic β cell dysfunction is critical to the development of type 2 diabetes (T2D). Our previous studies suggested that C3aR1 on β cells promotes insulin secretion and cell survival. However, as C3aR1 is expressed on many other cell types including within the islets, whole-body C3aR1 knockout models confound the analyses of direct impacts on β cells. METHODS: To clarify the role of C3aR1 in β cells under T2D conditions, we generated β cell-specific C3aR1 knockout mice. We assessed glucose homeostasis, focusing on β cell function and mass under metabolic stress conditions, to interrogate the effects of C3aR1 on β cells in a mouse model of T2D. We performed proteomic analyses on islets from control and β cell-specific C3aR1 knockout mice. To determine potential translational relevance, C3AR1 was assessed alongside glucose-stimulated insulin secretion in human islets. RESULTS: We show that the complement receptor C3aR1 on β cells plays an essential role in maintaining β cell homeostasis, especially under the metabolic duress of obesity and T2D. Male mice with β cell specific deletion of C3ar1 (β-C3aR1 KO) exhibit worse glucose tolerance and lower insulin levels when fed regular or high fat diet. Under high fat diet, β-C3aR1 KO also have diminished β cell mass. Islets from β-C3aR1 KO mice demonstrate impaired insulin secretion. β cells lacking C3aR1 display increased susceptibility to lipotoxicity-mediated cell death. Markers of β cell identity are decreased in β-C3aR1 KO mice while stress markers are elevated. Disruption of C3ar1 on β cells ablates the insulin secretory response to C3a, establishing a signaling axis between C3a and β cell-derived C3aR1. Islet proteomic analyses highlight the MAPK pathway and mitochondrial dysfunction with C3aR1 loss in β cells. Finally, we show that C3AR1 is positively correlated with insulin secretion in human islets. CONCLUSIONS: These findings indicate that C3aR1 expression on β cells is necessary to maintain optimal β cell function and preserve β cell mass in T2D.","journal":"Molecular Metabolism","year":2025,"id":514687,"datarank":0.31191623125197543,"base_score":2.0794415416798357,"endowment":2.0794415416798357,"self_citation_contribution":0.31191623125197543,"citation_network_contribution":0.0,"self_endowment_contribution":0.31191623125197543,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9602,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1024276,"name":"Ang Li","orcid":"0000-0003-0359-3510","position":1,"is_corresponding":false},{"id":468244,"name":"Ankit Gilani","orcid":"0000-0002-5100-0110","position":2,"is_corresponding":false},{"id":623448,"name":"Alfonso Rubio‐Navarro","orcid":"0000-0001-5677-3123","position":3,"is_corresponding":false},{"id":808606,"name":"Charles David Warren","orcid":null,"position":4,"is_corresponding":false},{"id":567460,"name":"Isabella Y. Kong","orcid":"0000-0002-7480-4525","position":5,"is_corresponding":false},{"id":844396,"name":"Jacob B. Geri","orcid":"0000-0002-9215-5610","position":6,"is_corresponding":false},{"id":581323,"name":"James C. Lo","orcid":"0000-0003-0244-1670","position":7,"is_corresponding":false},{"id":1333971,"name":"Renan Pereira de Lima","orcid":"0000-0001-9653-7037","position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:48:29.165853Z","pmid":"40189102","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":[]}