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The prevalence of diabetic cardiomyopathy in the population is 1.1%. We previously showed that SGLT1 is expressed in cardiomyocytes and is further upregulated in diabetic cardiomyopathy and other forms of heart failure. In this study, we sought to determine the mechanisms by which cardiac SGLT1 contributes to the pathophysiology of heart failure in diabetes, obesity, and insulin resistance. We determined whether transgenic mice with cardiomyocyte-specific knockdown of SGLT1 (TG\n                    <jats:sup>SGLT1-DOWN<\/jats:sup>\n                    ) had attenuation of cardiomyopathy after induction of obesity and insulin resistance by exposure to a high fat diet (HFD) from ages 8\u201328\u00a0weeks. TG\n                    <jats:sup>SGLT1-DOWN<\/jats:sup>\n                    mice and wildtype (WT) littermates exhibited similar increases in body weight and blood glucose after exposure to HFD. Nevertheless, TG\n                    <jats:sup>SGLT1-DOWN<\/jats:sup>\n                    mice exhibited attenuation of cardiomyopathy, manifested by less hypertrophy, systolic and diastolic dysfunction, fibrosis, nicotinamide adenine dinucleotide phosphate oxidase 2 (Nox2) activation, and reactive oxygen species (ROS) production. In vivo hyperinsulinemia and in vitro exposure of cardiomyocytes to high glucose or insulin led to an increase in SGLT1 expression by increasing binding of the transcription factors HNF-1 and Sp1 to the SGLT1 gene (\n                    <jats:italic>Slc5a1<\/jats:italic>\n                    ), and the transcript stabilizer HuR to SGLT1 mRNA. SGLT1 may contribute to cardiac injury in obesity and insulin resistance by stimulating ROS through its interaction with EGFR. SGLT1 may represent a therapeutic target for inhibition to prevent or to reverse diabetic cardiomyopathy.\n                  <\/jats:p>","DOI":"10.1007\/s00395-025-01136-7","type":"journal-article","created":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T07:45:59Z","timestamp":1757576759000},"page":"1193-1207","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Cardiac sodium-glucose co-transporter 1 (SGLT1) contributes to heart failure in a mouse model of diabetic cardiomyopathy"],"prefix":"10.1007","volume":"120","author":[{"given":"Zhao","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney","family":"Freiberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meredith L.","family":"Music","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Nacos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph P.","family":"Phillips","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adil","family":"Hassan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamel","family":"Shibbani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanah S.","family":"Munir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vooha K.","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke","family":"Halligan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mia E.","family":"Michel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin F.","family":"London","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ngan","family":"Bui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Cicha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Buffard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. 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