{"doi":"10.1016/j.redox.2025.103566","title":"NRF2 deficiency leads to inadequate beta cell adaptation during pregnancy and gestational diabetes","abstract":"The late stages of mammalian pregnancy are accompanied by a mild increase in insulin resistance likely due to enhanced glucose demand of the growing fetus. Therefore, as an adaptive process to maintain euglycemia during pregnancy, maternal β-cell mass expands leading to increased insulin release. Defects in functional β-cell adaptive expansion during pregnancy can lead to gestational diabetes mellitus (GDM). While the exact mechanisms that promote GDM are poorly understood, GDM is associated with inadequate functional β-cell mass expansion and with a systematic increase of oxidative stress. Here, we show that NRF2 levels are upregulated in mouse β-cells at gestational day 15 (GD15). Inducible β-cell-specific Nrf2 deleted (βNrf2KO) mice display reduced β-cell proliferation, increased β-cell oxidative stress and lipid peroxidation, compromised β-cell function, and elevated β-cell death, leading to impaired β-cell mass expansion and dysregulated glucose homeostasis towards the end of pregnancy. Importantly, the gestational hormone 17-β-estradiol (E2) increases NRF2 levels, and downregulation of NRF2 suppresses E2-induced protection of β-cells against oxidative stress, suggesting that E2 exerts its antioxidant effects through activation of NRF2 signaling in β-cells. Collectively, these data highlight the critical role of NRF2 in regulating oxidative stress during the adaptive response of β-cells in pregnancy and identify NRF2 as a potential therapeutic target for GDM treatment.","journal":"Redox Biology","year":2025,"id":516489,"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":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.948,"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":381016,"name":"Luca Lambertini","orcid":"0000-0003-3326-219X","position":1,"is_corresponding":false},{"id":1177388,"name":"Isabelle Tse","orcid":null,"position":2,"is_corresponding":false},{"id":1382273,"name":"Sriya Dodda","orcid":null,"position":3,"is_corresponding":false},{"id":310887,"name":"Adolfo Garcı́a-Ocaña","orcid":"0000-0002-6883-6176","position":4,"is_corresponding":false},{"id":381015,"name":"Donald K. Scott","orcid":"0000-0002-1414-9223","position":5,"is_corresponding":false},{"id":495587,"name":"Sharon Baumel-Alterzon","orcid":"0000-0002-5283-4707","position":6,"is_corresponding":false},{"id":808382,"name":"Fatema Haidery","orcid":null,"position":0,"is_corresponding":true}],"reference_count":103,"raw_metadata":null,"created_at":"2026-07-19T02:48:49.486328Z","pmid":"40054060","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":[]}