{"doi":"10.7554/elife.79422","title":"β-cell deletion of the PKm1 and PKm2 isoforms of pyruvate kinase in mice reveals their essential role as nutrient sensors for the KATP channel","abstract":"Pyruvate kinase (PK) and the phosphoenolpyruvate (PEP) cycle play key roles in nutrient-stimulated K ATP channel closure and insulin secretion. To identify the PK isoforms involved, we generated mice lacking β-cell PKm1, PKm2, and mitochondrial PEP carboxykinase (PCK2) that generates mitochondrial PEP. Glucose metabolism was found to generate both glycolytic and mitochondrially derived PEP, which triggers K ATP closure through local PKm1 and PKm2 signaling at the plasma membrane. Amino acids, which generate mitochondrial PEP without producing glycolytic fructose 1,6-bisphosphate to allosterically activate PKm2, signal through PKm1 to raise ATP/ADP, close K ATP channels, and stimulate insulin secretion. Raising cytosolic ATP/ADP with amino acids is insufficient to close K ATP channels in the absence of PK activity or PCK2, indicating that K ATP channels are primarily regulated by PEP that provides ATP via plasma membrane-associated PK, rather than mitochondrially derived ATP. Following membrane depolarization, the PEP cycle is involved in an ‘off-switch’ that facilitates K ATP channel reopening and Ca 2+ extrusion, as shown by PK activation experiments and β-cell PCK2 deletion, which prolongs Ca 2+ oscillations and increases insulin secretion. In conclusion, the differential response of PKm1 and PKm2 to the glycolytic and mitochondrial sources of PEP influences the β-cell nutrient response, and controls the oscillatory cycle regulating insulin secretion.","journal":"eLife","year":2022,"id":238367,"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":55,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9571,"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":258184,"name":"Thuong Ho","orcid":"0000-0003-1855-1110","position":1,"is_corresponding":false},{"id":258185,"name":"Evgeniy Potapenko","orcid":"0000-0001-7045-6394","position":2,"is_corresponding":false},{"id":260984,"name":"Sophia M. Sdao","orcid":null,"position":3,"is_corresponding":false},{"id":75637,"name":"Shih Ming Huang","orcid":"0000-0002-5070-1732","position":4,"is_corresponding":false},{"id":258182,"name":"Sophie L. Lewandowski","orcid":"0000-0002-2838-7054","position":5,"is_corresponding":false},{"id":258187,"name":"Halena R. VanDeusen","orcid":"0000-0002-7950-2251","position":6,"is_corresponding":false},{"id":74591,"name":"Shawn M. Davidson","orcid":"0000-0002-3475-0382","position":7,"is_corresponding":false},{"id":257018,"name":"Rebecca Cardone","orcid":null,"position":8,"is_corresponding":false},{"id":325894,"name":"Marc Prentki","orcid":"0000-0002-0499-3324","position":9,"is_corresponding":false},{"id":254925,"name":"Richard G. Kibbey","orcid":"0000-0001-6768-3473","position":10,"is_corresponding":false},{"id":258194,"name":"Matthew J. Merrins","orcid":"0000-0003-1599-9227","position":11,"is_corresponding":false},{"id":258183,"name":"Hannah R. Foster","orcid":"0000-0003-4683-6180","position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":null,"created_at":"2026-07-19T00:22:26.932537Z","pmid":"35997256","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":[]}