{"doi":"10.1172/jci.insight.166713","title":"Cardiac gene therapy treats diabetic cardiomyopathy and lowers blood glucose","abstract":"Diabetic cardiomyopathy, an increasingly global epidemic and a major cause of heart failure with preserved ejection fraction (HFpEF), is associated with hyperglycemia, insulin resistance, and intracardiomyocyte calcium mishandling. Here we identify that, in db/db mice with type 2 diabetes-induced 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.","journal":"JCI Insight","year":2023,"id":325902,"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":30,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9597,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":731206,"name":"Bradley Richmond","orcid":"0009-0001-3868-0887","position":1,"is_corresponding":false},{"id":232398,"name":"Ahmad A. Cluntun","orcid":"0000-0001-7612-8375","position":2,"is_corresponding":false},{"id":833690,"name":"Ryan Bia","orcid":"0000-0002-1979-7051","position":3,"is_corresponding":false},{"id":820773,"name":"Maureen A. Walsh","orcid":"0000-0003-0600-9455","position":4,"is_corresponding":false},{"id":1044250,"name":"Kikuyo Shaw","orcid":"0000-0002-2272-0645","position":5,"is_corresponding":false},{"id":355395,"name":"J. David Symons","orcid":"0000-0003-2021-4770","position":6,"is_corresponding":false},{"id":644858,"name":"Sarah Franklin","orcid":"0000-0002-2958-1879","position":7,"is_corresponding":false},{"id":232415,"name":"Jared Rutter","orcid":"0000-0002-2710-9765","position":8,"is_corresponding":false},{"id":262194,"name":"Katsuhiko Funai","orcid":"0000-0003-3802-4756","position":9,"is_corresponding":false},{"id":344072,"name":"Robin M. Shaw","orcid":"0000-0001-7429-6092","position":10,"is_corresponding":false},{"id":344071,"name":"TingTing Hong","orcid":"0000-0002-0243-5046","position":11,"is_corresponding":false},{"id":912195,"name":"Jing Li","orcid":"0000-0002-8311-7698","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-19T01:08:28.266998Z","pmid":"37639557","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":[]}