{"doi":"10.1172/jci142365","title":"Electrogenic sodium bicarbonate cotransporter NBCe1 regulates pancreatic β cell function in type 2 diabetes","abstract":"Pancreatic β cell failure in type 2 diabetes mellitus (T2DM) is attributed to perturbations of the β cell's transcriptional landscape resulting in impaired glucose-stimulated insulin secretion. Recent studies identified SLC4A4 (a gene encoding an electrogenic Na+-coupled HCO3- cotransporter and intracellular pH regulator, NBCe1) as one of the misexpressed genes in β cells of patients with T2DM. Thus, in the current study, we set out to test the hypothesis that misexpression of SLC4A4/NBCe1 in T2DM β cells contributes to β cell dysfunction and impaired glucose homeostasis. To address this hypothesis, we first confirmed induction of SLC4A4/NBCe1 expression in β cells of patients with T2DM and demonstrated that its expression was associated with loss of β cell transcriptional identity, intracellular alkalinization, and β cell dysfunction. In addition, we generated a β cell-selective Slc4a4/NBCe1-KO mouse model and found that these mice were protected from diet-induced metabolic stress and β cell dysfunction. Importantly, improved glucose tolerance and enhanced β cell function in Slc4a4/NBCe1-deficient mice were due to augmented mitochondrial function and increased expression of genes regulating β cell identity and function. These results suggest that increased β cell expression of SLC4A4/NBCe1 in T2DM plays a contributory role in promotion of β cell failure and should be considered as a potential therapeutic target.","journal":"Journal of Clinical Investigation","year":2021,"id":169509,"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":29,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9471,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":701290,"name":"Heather L. Holmes","orcid":null,"position":1,"is_corresponding":false},{"id":265609,"name":"Kuntol Rakshit","orcid":null,"position":2,"is_corresponding":false},{"id":473668,"name":"Naureen Javeed","orcid":"0000-0003-0833-9239","position":3,"is_corresponding":false},{"id":429704,"name":"Tracy K. Her","orcid":"0000-0002-6335-7651","position":4,"is_corresponding":false},{"id":700488,"name":"Alison Stiller","orcid":"0009-0007-6320-4405","position":5,"is_corresponding":false},{"id":473669,"name":"Satish Sen","orcid":"0000-0002-0950-9722","position":6,"is_corresponding":false},{"id":701291,"name":"Gary E. Shull","orcid":null,"position":7,"is_corresponding":false},{"id":245519,"name":"Y. S. Prakash","orcid":"0000-0002-2968-224X","position":8,"is_corresponding":false},{"id":470102,"name":"Michael F. Romero","orcid":"0000-0002-1555-7835","position":9,"is_corresponding":false},{"id":241936,"name":"Aleksey V. Matveyenko","orcid":"0000-0001-7761-4842","position":10,"is_corresponding":false},{"id":281311,"name":"Matthew Brown","orcid":"0000-0001-7429-2657","position":0,"is_corresponding":true}],"reference_count":92,"raw_metadata":null,"created_at":"2026-07-18T23:46:15.560174Z","pmid":"34623331","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":[]}