Empagliflozin Increases Cardiac Energy Production in Diabetes: Novel Translational Insights Into the Heart Failure Benefits of SGLT2 Inhibitors
SGLT2 inhibitors have profound benefits on reducing heart failure and cardiovascular mortality in individuals with type 2 diabetes, although the mechanism(s) of this benefit remain poorly understood. Because changes in cardiac bioenergetics play a critical role in the pathophysiology of heart failur...
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| Vydáno v: | JACC. Basic to translational science Ročník 3; číslo 5; s. 575 - 587 |
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| Hlavní autoři: | , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
| Vydáno: |
United States
Elsevier
01.10.2018
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| Témata: | |
| ISSN: | 2452-302X, 2452-302X |
| On-line přístup: | Získat plný text |
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| Shrnutí: | SGLT2 inhibitors have profound benefits on reducing heart failure and cardiovascular mortality in individuals with type 2 diabetes, although the mechanism(s) of this benefit remain poorly understood. Because changes in cardiac bioenergetics play a critical role in the pathophysiology of heart failure, the authors evaluated cardiac energy production and substrate use in diabetic mice treated with the SGTL2 inhibitor, empagliflozin. Empagliflozin treatment of diabetic
mice prevented the development of cardiac failure. Glycolysis, and the oxidation of glucose, fatty acids and ketones were measured in the isolated working heart perfused with 5 mmol/l glucose, 0.8 mmol/l palmitate, 0.5 mmol/l ß-hydroxybutyrate (ßOHB), and 500 μU/ml insulin. In vehicle-treated
mice, cardiac glucose oxidation rates were decreased by 61%, compared with control mice, but only by 43% in empagliflozin-treated diabetic mice. Interestingly, cardiac ketone oxidation rates in
mice decreased to 45% of the rates seen in control mice, whereas a similar decrease (43%) was seen in empagliflozin-treated
mice. Overall cardiac adenosine triphosphate (ATP) production rates decreased by 36% in
vehicle-treated hearts compared with control mice, with fatty acid oxidation providing 42%, glucose oxidation 26%, ketone oxidation 10%, and glycolysis 22% of ATP production in
mouse hearts. In empagliflozin-treated
mice, cardiac ATP production rates increased by 31% compared with
vehicle-treated mice, primarily due to a 61% increase in the contribution of glucose oxidation to energy production. Cardiac efficiency (cardiac work/O
consumed) decreased by 28% in
vehicle-treated hearts, compared with control hearts, and empagliflozin did not increase cardiac efficiency per se. Because ketone oxidation was impaired in
mouse hearts, the authors determined whether this contributed to the decrease in cardiac efficiency seen in the
mouse hearts. Addition of 600 μmol/l ßOHB to d
mouse hearts perfused with 5 mmol/l glucose, 0.8 mmol/l palmitate, and 100 μU/ml insulin increased ketone oxidation rates, but did not decrease either glucose oxidation or fatty acid oxidation rates. The presence of ketones did not increase cardiac efficiency, but did increase ATP production rates, due to the additional contribution of ketone oxidation to energy production. The authors conclude that empagliflozin treatment is associated with an increase in ATP production, resulting in an enhanced energy status of the heart. |
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| Bibliografie: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Drs. Verma, Rawat, and Ho have contributed equally to this work. This paper is published simultaneously with the proceedings of the European Society of Cardiology 2018 Meeting. |
| ISSN: | 2452-302X 2452-302X |
| DOI: | 10.1016/j.jacbts.2018.07.006 |