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SGLT2 inhibition alters substrate utilization and mitochondrial redox in healthy and failing rat hearts
Leigh Goedeke, … , Lawrence H. Young, Gerald I. Shulman
Leigh Goedeke, … , Lawrence H. Young, Gerald I. Shulman
Published December 16, 2024
Citation Information: J Clin Invest. 2024;134(24):e176708. https://doi.org/10.1172/JCI176708.
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Research Article Cardiology Metabolism Article has an altmetric score of 75

SGLT2 inhibition alters substrate utilization and mitochondrial redox in healthy and failing rat hearts

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Abstract

Previous studies highlight the potential for sodium-glucose cotransporter type 2 (SGLT2) inhibitors (SGLT2i) to exert cardioprotective effects in heart failure by increasing plasma ketones and shifting myocardial fuel utilization toward ketone oxidation. However, SGLT2i have multiple in vivo effects and the differential impact of SGLT2i treatment and ketone supplementation on cardiac metabolism remains unclear. Here, using gas chromatography–mass spectrometry (GC-MS) and liquid chromatography–tandem mass spectrometry (LC-MS/MS) methodology combined with infusions of [13C6]glucose or [13C4]βOHB, we demonstrate that acute SGLT2 inhibition with dapagliflozin shifts relative rates of myocardial mitochondrial metabolism toward ketone oxidation, decreasing pyruvate oxidation with little effect on fatty acid oxidation in awake rats. Shifts in myocardial ketone oxidation persisted when plasma glucose levels were maintained. In contrast, acute βOHB infusion similarly augmented ketone oxidation, but markedly reduced fatty acid oxidation and did not alter glucose uptake or pyruvate oxidation. After inducing heart failure, dapagliflozin increased relative rates of ketone and fatty acid oxidation, but decreased pyruvate oxidation. Dapagliflozin increased mitochondrial redox and reduced myocardial oxidative stress in heart failure, which was associated with improvements in left ventricular ejection fraction after 3 weeks of treatment. Thus, SGLT2i have pleiotropic effects on systemic and heart metabolism, which are distinct from ketone supplementation and may contribute to the long-term cardioprotective benefits of SGLT2i.

Authors

Leigh Goedeke, Yina Ma, Rafael C. Gaspar, Ali Nasiri, Jieun Lee, Dongyan Zhang, Katrine Douglas Galsgaard, Xiaoyue Hu, Jiasheng Zhang, Nicole Guerrera, Xiruo Li, Traci LaMoia, Brandon T. Hubbard, Sofie Haedersdal, Xiaohong Wu, John Stack, Sylvie Dufour, Gina Marie Butrico, Mario Kahn, Rachel J. Perry, Gary W. Cline, Lawrence H. Young, Gerald I. Shulman

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Figure 5

Acute dapagliflozin treatment reduces and increases relative rates of glucose and βOHB oxidation, respectively, in the ischemic/infarct area and nonischemic myocardium remote from the infarct area 2 weeks after MI.

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Acute dapagliflozin treatment reduces and increases relative rates of gl...
(A–F) Glucose uptake, relative rates of myocardial pyruvate oxidation (VPDH) to total mitochondrial oxidation (VCS), and relative rates of βOHB oxidation (VBDH) to total mitochondrial oxidation (VCS) in the ischemic/infarct region (A–C) and nonischemic myocardium remote from the infarct area (D–F) in chow-fed male rats 2 weeks after MI or sham surgery. (G–I) Representative Western blot analysis of GLUT1 and GLUT4 (G), pPDH/PDH (H), and BDH1 and SCOT (I) in the LV of sham and MI rats treated as in A–F. HSP90 was used as a loading control. Quantification of blots shown in the right panels. (J) Correlation of plasma βOHB and VBDH/VCS in rats treated as in A–F. In panels A–J, n = 10, 8, 10, 9 (A); n = 10, 12, 7, 6 (B); n = 12, 12, 10, 10 (C); n = 11, 8, 6, 5 (D); n = 7, 9, 7, 9 (E); n = 11, 12, 7, 6 (F); n = 6 per group (G–I); and n = 8, 7, 7, 9 (J). All data are represented as mean ± SEM. P < 0.05 by 1-way ANOVA with Bonferroni’s corrections for multiple comparisons.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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