Journal article
Cardiac sodium-glucose co-transporter 1 (SGLT1) contributes to heart failure in a mouse model of diabetic cardiomyopathy
Basic research in cardiology, Vol.120(6), pp.1193-1207
12/2025
DOI: 10.1007/s00395-025-01136-7
PMCID: PMC12680731
PMID: 40932483
Appears in UI Libraries Support Open Access
Abstract
Diabetes mellitus can lead to a cardiomyopathy independent of other risk factors such as coronary artery disease and hypertension, in up to 75% of patients. 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
) had attenuation of cardiomyopathy after induction of obesity and insulin resistance by exposure to a high fat diet (HFD) from ages 8-28 weeks. TG
mice and wildtype (WT) littermates exhibited similar increases in body weight and blood glucose after exposure to HFD. Nevertheless, TG
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 (Slc5a1), 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.
Details
- Title: Subtitle
- Cardiac sodium-glucose co-transporter 1 (SGLT1) contributes to heart failure in a mouse model of diabetic cardiomyopathy
- Creators
- Zhao Li - Hartford Financial ServicesSydney Freiberg - Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine and Abboud Cardiovascular Research Center, University of Iowa, 25 South Grand Avenue, 1191D ML, Iowa City, IA, 52242, USAMeredith L Music - University of IowaLina Gu - University of IowaSarah Nacos - University of IowaJoseph P Phillips - University of IowaAdil Hassan - University of IowaKamel Shibbani - University of IowaSanah S Munir - Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine and Abboud Cardiovascular Research Center, University of Iowa, 25 South Grand Avenue, 1191D ML, Iowa City, IA, 52242, USAVooha K Kumar - Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine and Abboud Cardiovascular Research Center, University of Iowa, 25 South Grand Avenue, 1191D ML, Iowa City, IA, 52242, USALuke Halligan - University of IowaMia E Michel - Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine and Abboud Cardiovascular Research Center, University of Iowa, 25 South Grand Avenue, 1191D ML, Iowa City, IA, 52242, USABenjamin F London - University of IowaNgan Bui - Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine and Abboud Cardiovascular Research Center, University of Iowa, 25 South Grand Avenue, 1191D ML, Iowa City, IA, 52242, USAMichael Cicha - University of IowaValerie Buffard - University of IowaE Dale Abel - University of IowaFerhaan Ahmad - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Basic research in cardiology, Vol.120(6), pp.1193-1207
- DOI
- 10.1007/s00395-025-01136-7
- PMID
- 40932483
- PMCID
- PMC12680731
- NLM abbreviation
- Basic Res Cardiol
- ISSN
- 1435-1803
- eISSN
- 1435-1803
- Publisher
- Springer Nature
- Grant note
- R01 HL135000 / NHLBI NIH HHS 15GRNT25650003 / American Heart Association 16POST27770035 / American Heart Association
- Language
- English
- Electronic publication date
- 09/11/2025
- Date published
- 12/2025
- Academic Unit
- Radiology; Molecular Physiology and Biophysics; Cardiology; Stead Family Department of Pediatrics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984962643402771
Metrics
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