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At present, their immunometabolic effects remain elusive.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>Slc5a2<\/jats:italic>\n                      -knockout mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      SGLT2-null mice exhibited better glucose tolerance and insulin sensitivity (blood glucose during IPGTT AUC 0\u201390 min 1175\u00a0\u00b1\u00a057.4 mmol\/l \u00d7 min, mean \u00b1 SEM) compared with control (AUC 0\u201390 min 1857\u00a0\u00b1\u00a0117.9 mmol\/l \u00d7 min,\n                      <jats:italic>p<\/jats:italic>\n                      =0.05) or dapagliflozin-treated mice (AUC 0\u201390 min 1506\u00a0\u00b1\u00a068.72 mmol\/l \u00d7 min,\n                      <jats:italic>p<\/jats:italic>\n                      =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 (\n                      <jats:italic>p<\/jats:italic>\n                      &lt;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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-025-06467-7","type":"journal-article","created":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T14:56:55Z","timestamp":1750431415000},"page":"2042-2056","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Effects of SGLT2 ablation or inhibition on corticosterone secretion in high-fat-fed mice: exploring a nexus with cytokine levels"],"prefix":"10.1007","volume":"68","author":[{"given":"Niki F.","family":"Brisnovali","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Franco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amira","family":"Abdelgawwad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hio Lam Phoebe","family":"Tsou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thong Huy","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"McDonald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Riva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6360-0343","authenticated-orcid":false,"given":"Guy A.","family":"Rutter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9316-6680","authenticated-orcid":false,"given":"Elina","family":"Akalestou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,20]]},"reference":[{"key":"6467_CR1","unstructured":"Diabetes UK. 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GAR is supported by a Wellcome Trust Investigator award (212625\/Z\/18\/Z), a UKRI-Medical Research Council (MRC) Programme grant (MR\/R022259\/1), NIH-NIDDK project grants (R01DK135268, 1R01DK139630-01A1 PI), a Breakthrough T1D (formerly known as JDRF) Team grant (CIHR-IRSC TDP-186358 and JDRF 4-SRA-2023-1182-S-N), CRCHUM start-up funds and an Innovation Canada John R. Evans Leader Award (CFI 42649). AR and HLPT are supported by the Foundation for Liver Research (London, UK). THC was funded by the National Institute for Health and Care Research Leicester Biomedical Research Centre.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"GAR has received grant funding from Sun Pharmaceuticals Inc. for whom he is a consultant. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"EA and AR designed the study and interpreted the data. NFB, IF, AA and HLPT were responsible for data acquisition and analysis. GAR contributed to the acquisition and interpretation of data. EA, THC, JM and AR performed data analysis. All authors contributed to drafting the manuscript and approved the final version. EA is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}