{"doi":"10.3390/ijms27010103","title":"TAS1R3 Regulates GTPase Signaling in Human Skeletal Muscle Cells for Glucose Uptake","abstract":"Taste receptor type 1 member 3 (TAS1R3) is a class C G protein-coupled receptor (GPCR) traditionally associated with taste perception. While its role in insulin secretion is established, its contribution to skeletal muscle glucose uptake, a process responsible for 70-80% of postprandial glucose disposal, remains unclear. TAS1R3 expression was assessed in skeletal muscle biopsies from non-diabetic and type 2 diabetes (T2D) donors using qPCR and immunoblotting. Functional studies in human LHCN-M2 myotubes involved TAS1R3 inhibition with lactisole or siRNA-mediated knockdown, followed by the measurement of insulin-stimulated glucose uptake using radiolabeled glucose assays. Rac1 activation and phospho-cofilin were analyzed by G-LISA and Western blotting, and Gαq/11 involvement was tested using YM-254890. TAS1R3 mRNA and protein levels were significantly reduced in T2D skeletal muscle. Pharmacological inhibition or the knockdown of TAS1R3 impaired insulin-stimulated glucose uptake in myotubes. TAS1R3 regulates skeletal muscle glucose uptake through a non-canonical insulin signaling pathway involving Rac1 and phospho-cofilin, independent of IRS1-AKT and Gαq/11 signaling. These findings identify TAS1R3 as a key determinant of Rac1-mediated glucose uptake and a potential therapeutic target for improving insulin sensitivity in T2D.","journal":"International Journal of Molecular Sciences","year":2025,"id":586608,"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":0.9665,"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":1083797,"name":"Rekha Balakrishnan","orcid":"0000-0002-9724-5578","position":1,"is_corresponding":false},{"id":241713,"name":"Karla E. Merz","orcid":"0000-0003-0094-9382","position":2,"is_corresponding":false},{"id":241714,"name":"Debbie C. Thurmond","orcid":"0000-0002-6303-4596","position":3,"is_corresponding":false},{"id":686587,"name":"Rajakrishnan Veluthakal","orcid":"0000-0002-4685-0647","position":4,"is_corresponding":false},{"id":1083798,"name":"Joseph M. Hoolachan","orcid":"0000-0002-8142-1469","position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":null,"created_at":"2026-07-19T02:59:32.191237Z","pmid":"41515983","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":[]}