{"doi":"10.1016/j.molmet.2021.101243","title":"Non-canonical NRF2 activation promotes a pro-diabetic shift in hepatic glucose metabolism","abstract":"OBJECTIVE: NRF2, a transcription factor that regulates cellular redox and metabolic homeostasis, plays a dual role in human disease. While it is well known that canonical intermittent NRF2 activation protects against diabetes-induced tissue damage, little is known regarding the effects of prolonged non-canonical NRF2 activation in diabetes. The goal of this study was to determine the role and mechanisms of prolonged NRF2 activation in arsenic diabetogenicity. METHODS: mice exposed to arsenic in the drinking water for 20 weeks. RESULTS: In contrast to canonical oxidative/electrophilic activation, prolonged non-canonical NRF2 activation via p62-mediated sequestration of KEAP1 increases carbohydrate flux through the polyol pathway, resulting in a pro-diabetic shift in glucose homeostasis. This p62- and NRF2-dependent increase in liver fructose metabolism and gluconeogenesis occurs through the upregulation of four novel NRF2 target genes, ketohexokinase (Khk), sorbitol dehydrogenase (Sord), triokinase/FMN cyclase (Tkfc), and hepatocyte nuclear factor 4 (Hnf4A). CONCLUSION: We demonstrate that NRF2 and p62 are essential for arsenic-mediated insulin resistance and glucose intolerance, revealing a pro-diabetic role for prolonged NRF2 activation in arsenic diabetogenesis.","journal":"Molecular Metabolism","year":2021,"id":170828,"datarank":0.49983067652628066,"base_score":3.332204510175204,"endowment":3.332204510175204,"self_citation_contribution":0.49983067652628066,"citation_network_contribution":0.0,"self_endowment_contribution":0.49983067652628066,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":27,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9572,"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":66207,"name":"Matthew Dodson","orcid":"0000-0002-3743-5476","position":1,"is_corresponding":false},{"id":703943,"name":"Hui Li","orcid":"0000-0002-2108-0201","position":2,"is_corresponding":false},{"id":228193,"name":"Cody J. Schmidlin","orcid":"0000-0002-0361-5890","position":3,"is_corresponding":false},{"id":637023,"name":"Aryatara Shakya","orcid":"0000-0001-5309-9436","position":4,"is_corresponding":false},{"id":300871,"name":"Yongyi Wei","orcid":"0000-0001-8730-117X","position":5,"is_corresponding":false},{"id":300875,"name":"Joe G. N. Garcia","orcid":"0000-0002-6934-0420","position":6,"is_corresponding":false},{"id":300874,"name":"Eli Chapman","orcid":"0000-0002-6310-1664","position":7,"is_corresponding":false},{"id":241179,"name":"Pawel R. Kiela","orcid":"0000-0002-0014-3517","position":8,"is_corresponding":false},{"id":335863,"name":"Qing-Yu Zhang","orcid":null,"position":9,"is_corresponding":false},{"id":244442,"name":"Eileen White","orcid":"0000-0003-2961-3065","position":10,"is_corresponding":false},{"id":334976,"name":"Xinxin Ding","orcid":"0000-0002-3448-9444","position":11,"is_corresponding":false},{"id":300873,"name":"Aikseng Ooi","orcid":"0000-0002-3451-0717","position":12,"is_corresponding":false},{"id":228195,"name":"Donna D. Zhang","orcid":"0000-0002-8972-697X","position":13,"is_corresponding":false},{"id":243313,"name":"Pengfei Liu","orcid":"0000-0002-4177-709X","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:46:24.040760Z","pmid":"33933676","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":[]}