{"doi":"10.1007/s00125-025-06467-7","title":"Effects of SGLT2 ablation or inhibition on corticosterone secretion in high-fat-fed mice: exploring a nexus with cytokine levels","abstract":"AIMS/HYPOTHESIS: Despite recent therapeutic advances, achieving optimal glycaemic control remains a challenge in managing type 2 diabetes. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as effective treatments by promoting urinary glucose excretion. However, the full scope of their mechanisms extends beyond glycaemic control. At present, their immunometabolic effects remain elusive. METHODS: To investigate the effects of SGLT2 inhibition or deletion, we compared the metabolic and immune phenotype between high-fat-diet-fed control mice, mice treated chronically with dapagliflozin, and total-body Slc5a2-knockout mice. RESULTS: SGLT2-null mice exhibited better glucose tolerance and insulin sensitivity (blood glucose during IPGTT AUC 0-90 min 1175 ± 57.4 mmol/l × min, mean ± SEM) compared with control (AUC 0-90 min 1857 ± 117.9 mmol/l × min, p=0.05) or dapagliflozin-treated mice (AUC 0-90 min 1506 ± 68.72 mmol/l × min, p=0.09), independent of glycosuria and body weight. Moreover, SGLT2-null mice demonstrated physiological regulation of corticosterone secretion, with lower morning levels than control mice (p<0.01). Systemic cytokine profiling also unveiled significant alterations in inflammatory mediators, particularly IL-6. Furthermore, unbiased proteomic analysis demonstrated downregulation of acute-phase proteins and upregulation of glutathione-related proteins, suggesting a role in the modulation of antioxidant responses. Conversely, IL-6 treatment increased SGLT2 expression in human kidney HK2 cells, suggesting a role for cytokines in the effects of hyperglycaemia. CONCLUSIONS/INTERPRETATION: Collectively, our data elucidate a potential interplay between SGLT2 activity, immune modulation and metabolic homeostasis, as well as a potential feedback loop between SGLT2 expression and cytokine concentration.","journal":"Diabetologia","year":2025,"id":568811,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9585,"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":1336268,"name":"Isabelle Franco","orcid":null,"position":1,"is_corresponding":false},{"id":1336269,"name":"Amira Abdelgawwad","orcid":null,"position":2,"is_corresponding":false},{"id":1335954,"name":"Hio Lam Phoebe Tsou","orcid":"0000-0001-7705-7820","position":3,"is_corresponding":false},{"id":1335955,"name":"Thong Huy Cao","orcid":"0000-0002-6559-0836","position":4,"is_corresponding":false},{"id":1473595,"name":"John E. McDonald","orcid":"0000-0002-2303-3329","position":5,"is_corresponding":false},{"id":1249830,"name":"Antonio Riva","orcid":"0000-0002-4974-2780","position":6,"is_corresponding":false},{"id":350920,"name":"Guy A. Rutter","orcid":"0000-0001-6360-0343","position":7,"is_corresponding":false},{"id":572619,"name":"Elina Akalestou","orcid":"0000-0001-9316-6680","position":8,"is_corresponding":false},{"id":1210711,"name":"Niki F. Brisnovali","orcid":null,"position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-19T02:56:55.795846Z","pmid":"40542280","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":[]}