{"doi":"10.1016/j.molmet.2020.101056","title":"Lactate activation of α-cell KATP channels inhibits glucagon secretion by hyperpolarizing the membrane potential and reducing Ca2+ entry","abstract":"Elevations in pancreatic α-cell intracellular Ca2+ ([Ca2+]i) lead to glucagon (GCG) secretion. Although glucose inhibits GCG secretion, how lactate and pyruvate control α-cell Ca2+ handling is unknown. Lactate enters cells through monocarboxylate transporters (MCTs) and is also produced during glycolysis by lactate dehydrogenase A (LDHA), an enzyme expressed in α-cells. As lactate activates ATP-sensitive K+ (KATP) channels in cardiomyocytes, lactate may also modulate α-cell KATP. Therefore, this study investigated how lactate signaling controls α-cell Ca2+ handling and GCG secretion. Mouse and human islets were used in combination with confocal microscopy, electrophysiology, GCG immunoassays, and fluorescent thallium flux assays to assess α-cell Ca2+ handling, Vm, KATP currents, and GCG secretion. Lactate-inhibited mouse (75 ± 25%) and human (47 ± 9%) α-cell [Ca2+]i fluctuations only under low-glucose conditions (1 mM) but had no effect on β- or δ-cells [Ca2+]i. Glyburide inhibition of KATP channels restored α-cell [Ca2+]i fluctuations in the presence of lactate. Lactate transport into α-cells via MCTs hyperpolarized mouse (14 ± 1 mV) and human (12 ± 1 mV) α-cell Vm and activated KATP channels. Interestingly, pyruvate showed a similar KATP activation profile and α-cell [Ca2+]i inhibition as lactate. Lactate-induced inhibition of α-cell [Ca2+]i influx resulted in reduced GCG secretion in mouse (62 ± 6%) and human (43 ± 13%) islets. These data demonstrate for the first time that lactate entry into α-cells through MCTs results in KATP activation, Vm hyperpolarization, reduced [Ca2+]i, and inhibition of GCG secretion. Thus, taken together, these data indicate that lactate either within α-cells and/or elevated in serum could serve as important modulators of α-cell function.","journal":"Molecular Metabolism","year":2020,"id":96636,"datarank":0.5416376868966337,"base_score":3.6109179126442243,"endowment":3.6109179126442243,"self_citation_contribution":0.5416376868966337,"citation_network_contribution":0.0,"self_endowment_contribution":0.5416376868966337,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":36,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9546,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":369839,"name":"Prasanna K. Dadi","orcid":"0000-0001-5377-5991","position":1,"is_corresponding":false},{"id":346921,"name":"Matthew T. Dickerson","orcid":"0000-0002-6187-3951","position":2,"is_corresponding":false},{"id":370584,"name":"Arya Y. Nakhe","orcid":null,"position":3,"is_corresponding":false},{"id":480010,"name":"Ariel S. Thorson","orcid":null,"position":4,"is_corresponding":false},{"id":369841,"name":"Charles M. Schaub","orcid":"0000-0002-3251-3455","position":5,"is_corresponding":false},{"id":369840,"name":"Sarah M. Graff","orcid":"0000-0003-2408-3683","position":6,"is_corresponding":false},{"id":478909,"name":"Jade Stanley","orcid":"0000-0002-2741-8437","position":7,"is_corresponding":false},{"id":480011,"name":"Roy S. Kondapavuluru","orcid":null,"position":8,"is_corresponding":false},{"id":328000,"name":"Jerod S. Denton","orcid":"0000-0003-0032-8586","position":9,"is_corresponding":false},{"id":345680,"name":"David A. Jacobson","orcid":"0000-0003-1816-5375","position":10,"is_corresponding":false},{"id":345676,"name":"Karolina E. Zaborska","orcid":"0000-0003-1218-5228","position":0,"is_corresponding":true}],"reference_count":88,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T22:35:06.014648Z","pmid":"32736089","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":[]}