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Published VersionCC BY V4.0, Open Access
Journal article
Sotagliflozin, a Dual SGLT 1/2 Inhibitor, improves cardiac outcomes in Normoglycemic Mouse Model of cardia pressure overload
Frontiers in Physiology, Vol.12, pp.1-13
2021
Abstract
Selective SGLT2 inhibition reduces the risk of worsening heart failure and cardiovascular death in patients with existing heart failure, irrespective of diabetic status. We aimed to investigate the effects of dual SGLT1/2 inhibition, using sotagliflozin, on cardiac outcomes in normal diet (ND) and high fat diet (HFD) mice with cardiac pressure overload. Five-week-old male C57BL/6J mice were randomized to receive a HFD (60% of calories from fat) or remain on ND for 12 weeks. One week later, transverse aortic constriction (TAC) was employed to induce cardiac pressure-overload (50% increase in right:left carotid pressure versus sham surgery), resulting in left ventricular hypertrophic remodeling and cardiac fibrosis, albeit preserved ejection fraction. At 4 weeks post-TAC, mice were treated for 7 weeks by oral gavage once daily with sotagliflozin (10 mg/kg body weight) or vehicle (0.1% tween 80). In ND mice, treatment with sotagliflozin attenuated cardiac hypertrophy and histological markers of cardiac fibrosis induced by TAC. These benefits were associated with profound diuresis and glucosuria, without shifts toward whole-body fatty acid utilization, increased circulating ketones, nor increased cardiac ketolysis. In HFD mice, sotagliflozin reduced the mildly elevated glucose and insulin levels but did not attenuate cardiac injury induced by TAC. HFD mice had vacuolation of proximal tubular cells, associated with less profound sotagliflozin-induced diuresis and glucosuria, which suggests dampened drug action. We demonstrate the utility of dual SGLT1/2 inhibition in treating cardiac injury induced by pressure overload in normoglycemic mice. Its efficacy in high fat-fed mice with mild hyperglycemia and compromised renal morphology requires further study.
Details
- Title
- Sotagliflozin, a Dual SGLT 1/2 Inhibitor, improves cardiac outcomes in Normoglycemic Mouse Model of cardia pressure overload
- Authors
- Sophia L. Young (Author) - The University of QueenslandLydia Ryan (Author) - The University of QueenslandThomas P Mullins (Author) - The University of QueenslandMelanie Flint (Author) - The University of QueenslandSarah E Steane (Author) - The University of QueenslandSarah L Walton (Author) - Monash UniversityHelle Bielefeldt-Ohmann (Author) - The University of QueenslandDavid A Carter (Author) - The University of QueenslandMelissa E Reichelt (Author) - The University of QueenslandLinda A Gallo (Author) - The University of Queensland
- Publication details
- Frontiers in Physiology, Vol.12, pp.1-13
- Publisher
- Frontiers Research Foundation
- Date published
- 2021
- DOI
- 10.3389/fphys.2021.738594
- ISSN
- 1664-042X
- Copyright note
- © 2021 Young, Ryan, Mullins, Flint, Steane, Walton, Bielefeldt-Ohmann, Carter, Reichelt and Gallo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
- Organisation Unit
- School of Health - Biomedicine; University of the Sunshine Coast, Queensland; School of Health and Behavioural Sciences - Legacy
- Language
- English
- Record Identifier
- 99620608502621
- Output Type
- Journal article
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