{"doi":"10.1152/ajpcell.00309.2020","title":"Hypoxia-inducible factor-1 mediates pancreatic β-cell dysfunction by intermittent hypoxia","abstract":"The role of hypoxia-inducible factor (HIF)-1 in pancreatic β-cell response to intermittent hypoxia (IH) was examined. Studies were performed on adult wild-type (WT), HIF-1α heterozygous (HET), β-cell-specific HIF-1 −/− mice and mouse insulinoma (MIN6) cells exposed to IH patterned after blood O 2 profiles during obstructive sleep apnea. WT mice treated with IH showed insulin resistance, and pancreatic β-cell dysfunction manifested as augmented basal insulin secretion, and impaired glucose-stimulated insulin secretion and these effects were absent in HIF-1α HET mice. IH increased HIF-1α expression and elevated reactive oxygen species (ROS) levels in β-cells of WT mice. The elevated ROS levels were due to transcriptional upregulation of NADPH oxidase (NOX)-4 mRNA, protein and enzymatic activity, and these responses were absent in HIF-1α HET mice as well as in β-HIF-1 −/− mice. IH-evoked β-cell responses were absent in adult WT mice treated with digoxin, an inhibitor of HIF-1α. MIN6 cells treated with in vitro IH showed enhanced basal insulin release and elevated HIF-1α protein expression, and these effects were abolished with genetic silencing of HIF-1α. IH increased NOX4 mRNA, protein, and enzyme activity in MIN6 cells and disruption of NOX4 function by siRNA or scavenging H 2 O 2 with polyethylene glycol catalase blocked IH-evoked enhanced basal insulin secretion. These results demonstrate that HIF-1-mediated transcriptional activation of NOX4 and the ensuing increase in H 2 O 2 contribute to IH-induced pancreatic β-cell dysfunction.","journal":"American Journal of Physiology-Cell Physiology","year":2020,"id":63223,"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":46,"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":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":334388,"name":"Xuefeng Shi","orcid":"0000-0002-4694-8759","position":1,"is_corresponding":false},{"id":335701,"name":"Shakil A. Khan","orcid":null,"position":2,"is_corresponding":false},{"id":334389,"name":"Benjamin Wang","orcid":"0000-0001-8691-9410","position":3,"is_corresponding":false},{"id":334390,"name":"Gregg L. Semenza","orcid":"0000-0002-0913-211X","position":4,"is_corresponding":false},{"id":235158,"name":"Nanduri R. Prabhakar","orcid":"0000-0003-4570-1380","position":5,"is_corresponding":false},{"id":235160,"name":"Jayasri Nanduri","orcid":"0000-0003-3984-7447","position":6,"is_corresponding":false},{"id":228251,"name":"Ning Wang","orcid":"0000-0003-1410-329X","position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-18T21:11:00.632961Z","pmid":"32936698","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":[]}