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Here we identify that, in db\/db mice with type 2 diabetes\u2013induced HFpEF, abnormal remodeling of cardiomyocyte transverse-tubule microdomains occurs with downregulation of the membrane scaffolding protein cardiac bridging integrator 1 (cBIN1). Transduction of cBIN1 by AAV9 gene therapy can restore transverse-tubule microdomains to normalize intracellular distribution of calcium-handling proteins and, surprisingly, glucose transporter 4 (GLUT4). Cardiac proteomics revealed that AAV9-cBIN1 normalized components of calcium handling and GLUT4 translocation machineries. Functional studies further identified that AAV9-cBIN1 normalized insulin-dependent glucose uptake in diabetic cardiomyocytes. Phenotypically, AAV9-cBIN1 rescued cardiac lusitropy, improved exercise intolerance, and ameliorated hyperglycemia in diabetic mice. Restoration of transverse-tubule microdomains can improve cardiac function in the setting of diabetic cardiomyopathy and can also improve systemic glycemic control.<\/jats:p>","DOI":"10.1172\/jci.insight.166713","type":"journal-article","created":{"date-parts":[[2023,8,28]],"date-time":"2023-08-28T15:04:21Z","timestamp":1693235061000},"source":"Crossref","is-referenced-by-count":31,"title":["Cardiac gene therapy treats diabetic cardiomyopathy and lowers blood glucose"],"prefix":"10.1172","volume":"8","author":[{"given":"Jing","family":"Li","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy,"},{"name":"Nora Eccles Harrison Cardiovascular Research and Training Institute,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley","family":"Richmond","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7612-8375","authenticated-orcid":true,"given":"Ahmad A.","family":"Cluntun","sequence":"additional","affiliation":[{"name":"Department of Biochemistry,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Bia","sequence":"additional","affiliation":[{"name":"Nora Eccles Harrison Cardiovascular Research and Training Institute,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0600-9455","authenticated-orcid":true,"given":"Maureen A.","family":"Walsh","sequence":"additional","affiliation":[{"name":"College of Health, Department of Nutrition and Integrative Physiology, Program in Molecular Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2272-0645","authenticated-orcid":true,"given":"Kikuyo","family":"Shaw","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2021-4770","authenticated-orcid":true,"given":"J. 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