{"doi":"10.1111/bph.15241","title":"Activation of AT<sub>2</sub> receptors prevents diabetic complications in female db/db mice by NO‐mediated mechanisms","abstract":"Background and Purpose The AT 2 receptor plays a role in metabolism by opposing the actions triggered by the AT 1 receptors. Activation of AT 2 receptors has been shown to enhance insulin sensitivity in both normal and insulin resistance animal models. In this study, we investigated the mechanism by which AT 2 receptors activation improves metabolism in diabetic mice. Experimental Approach Female diabetic (db/db) and non‐diabetic (db/+) mice were treated for 1 month with the selective AT 2 agonist, compound 21 (C21, 0.3 mg·kg −1 ·day −1 , s.c.). To evaluate whether the effects of C21 depend on NO production, a subgroup of mice was treated with C21 plus a sub‐pressor dose of the NOS inhibitor l ‐NAME (0.1 mg·ml −1 , drinking water). Key Results C21‐treated db/db mice displayed improved glucose and pyruvate tolerance compared with saline‐treated db/db mice. Also, C21‐treated db/db mice showed reduced liver weight and decreased hepatic lipid accumulation compared with saline‐treated db/db mice. Insulin signalling analysis showed increased phosphorylation of the insulin receptor, Akt and FOXO1 in the livers of C21‐treated db/db mice compared with saline‐treated counterparts. These findings were associated with increased adiponectin levels in plasma and adipose tissue and reduced adipocyte size in inguinal fat. The beneficial effects of AT 2 receptors activation were associated with increased eNOS phosphorylation and higher levels of NO metabolites and were abolished by l ‐NAME. Conclusion and Implications Chronic C21 infusion exerts beneficial metabolic effects in female diabetic db/db mice, alleviating type 2 diabetes complications, through a mechanism that involves NO production.","journal":"British Journal of Pharmacology","year":2020,"id":86272,"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":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9685,"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":323109,"name":"Luciana C. Veiras","orcid":"0000-0002-4635-7772","position":1,"is_corresponding":false},{"id":440007,"name":"Justin Z. Y. Shen","orcid":"0000-0002-4279-9127","position":2,"is_corresponding":false},{"id":323110,"name":"Ellen A. Bernstein","orcid":"0000-0003-3597-9653","position":3,"is_corresponding":false},{"id":440910,"name":"D. Quiroga","orcid":null,"position":4,"is_corresponding":false},{"id":338693,"name":"U. Muscha Steckelings","orcid":"0000-0002-5430-4275","position":5,"is_corresponding":false},{"id":440008,"name":"Kenneth E. Bernstein","orcid":"0000-0001-8097-3272","position":6,"is_corresponding":false},{"id":323111,"name":"Jorge F. Giani","orcid":"0000-0003-0481-6595","position":7,"is_corresponding":false},{"id":440006,"name":"Fernando P. Dominici","orcid":"0000-0002-4351-0057","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-18T21:58:41.997408Z","pmid":"32851652","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":[]}