Sotagliflozin, a Dual SGLT1/2 Inhibitor, Improves Cardiac Outcomes in a Normoglycemic Mouse Model of Cardiac Pressure Overload
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 h...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-09-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2021.738594/full |
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| author | Sophia L. Young Sophia L. Young Lydia Ryan Lydia Ryan Thomas P. Mullins Thomas P. Mullins Melanie Flint Sarah E. Steane Sarah L. Walton Helle Bielefeldt-Ohmann David A. Carter Melissa E. Reichelt Linda A. Gallo Linda A. Gallo |
| author_facet | Sophia L. Young Sophia L. Young Lydia Ryan Lydia Ryan Thomas P. Mullins Thomas P. Mullins Melanie Flint Sarah E. Steane Sarah L. Walton Helle Bielefeldt-Ohmann David A. Carter Melissa E. Reichelt Linda A. Gallo Linda A. Gallo |
| author_sort | Sophia L. Young |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-16T23:59:27Z |
| format | Article |
| id | doaj.art-3d8d2e4e85a44d89a8f35e1262506864 |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-12-16T23:59:27Z |
| publishDate | 2021-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-3d8d2e4e85a44d89a8f35e12625068642022-12-21T22:11:07ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2021-09-011210.3389/fphys.2021.738594738594Sotagliflozin, a Dual SGLT1/2 Inhibitor, Improves Cardiac Outcomes in a Normoglycemic Mouse Model of Cardiac Pressure OverloadSophia L. Young0Sophia L. Young1Lydia Ryan2Lydia Ryan3Thomas P. Mullins4Thomas P. Mullins5Melanie Flint6Sarah E. Steane7Sarah L. Walton8Helle Bielefeldt-Ohmann9David A. Carter10Melissa E. Reichelt11Linda A. Gallo12Linda A. Gallo13School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, AustraliaMater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, QLD, AustraliaSchool of Biomedical Sciences, The University of Queensland, St Lucia, QLD, AustraliaMater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, QLD, AustraliaSchool of Biomedical Sciences, The University of Queensland, St Lucia, QLD, AustraliaMater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, QLD, AustraliaSchool of Biomedical Sciences, The University of Queensland, St Lucia, QLD, AustraliaSchool of Biomedical Sciences, The University of Queensland, St Lucia, QLD, AustraliaCardiovascular Disease Program, Department of Physiology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, AustraliaSchool of Veterinary Science, The University of Queensland, Gatton, QLD, AustraliaInstitute for Molecular Biosciences, The University of Queensland, St Lucia, QLD, AustraliaSchool of Biomedical Sciences, The University of Queensland, St Lucia, QLD, AustraliaSchool of Biomedical Sciences, The University of Queensland, St Lucia, QLD, AustraliaMater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, QLD, AustraliaSelective 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.https://www.frontiersin.org/articles/10.3389/fphys.2021.738594/fullenergy expenditureenergy intakeproximal tubular cell damagecardiac hypertrophycardiovasclar diseaseheart failure |
| spellingShingle | Sophia L. Young Sophia L. Young Lydia Ryan Lydia Ryan Thomas P. Mullins Thomas P. Mullins Melanie Flint Sarah E. Steane Sarah L. Walton Helle Bielefeldt-Ohmann David A. Carter Melissa E. Reichelt Linda A. Gallo Linda A. Gallo Sotagliflozin, a Dual SGLT1/2 Inhibitor, Improves Cardiac Outcomes in a Normoglycemic Mouse Model of Cardiac Pressure Overload Frontiers in Physiology energy expenditure energy intake proximal tubular cell damage cardiac hypertrophy cardiovasclar disease heart failure |
| title | Sotagliflozin, a Dual SGLT1/2 Inhibitor, Improves Cardiac Outcomes in a Normoglycemic Mouse Model of Cardiac Pressure Overload |
| title_full | Sotagliflozin, a Dual SGLT1/2 Inhibitor, Improves Cardiac Outcomes in a Normoglycemic Mouse Model of Cardiac Pressure Overload |
| title_fullStr | Sotagliflozin, a Dual SGLT1/2 Inhibitor, Improves Cardiac Outcomes in a Normoglycemic Mouse Model of Cardiac Pressure Overload |
| title_full_unstemmed | Sotagliflozin, a Dual SGLT1/2 Inhibitor, Improves Cardiac Outcomes in a Normoglycemic Mouse Model of Cardiac Pressure Overload |
| title_short | Sotagliflozin, a Dual SGLT1/2 Inhibitor, Improves Cardiac Outcomes in a Normoglycemic Mouse Model of Cardiac Pressure Overload |
| title_sort | sotagliflozin a dual sglt1 2 inhibitor improves cardiac outcomes in a normoglycemic mouse model of cardiac pressure overload |
| topic | energy expenditure energy intake proximal tubular cell damage cardiac hypertrophy cardiovasclar disease heart failure |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2021.738594/full |
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