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

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

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 1

Acute dapagliflozin treatment significantly increases relative rates of

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Acute dapagliflozin treatment significantly increases relative rates of ...
βOHB oxidation at the expense of pyruvate oxidation in chow-fed male rats. (A) Outline of study design. Rats were given an intravenous bolus of 14C[2-DG] during the last 20 minutes of the infusion. (B–K) Weight change (B), plasma glucose (C), plasma insulin (D), plasma glucagon (E), plasma NEFAs (F), whole-body βOHB turnover (G), plasma βOHB (H), relative rates of myocardial βOHB oxidation (VBDH) to total mitochondrial oxidation (VCS) (I), myocardial glucose uptake (J), and relative rates of myocardial pyruvate oxidation (VPDH) to total mitochondrial oxidation (VCS) (K) in chow-fed male rats treated as in A. In panels (B–K), n = 24, 20, 20 (B and D and F); n = 22, 20, 20 (C); n = 24, 19, 19 (E); n = 11, 10, 11 (G); n = 22, 19, 20 (H); n = 12, 10, 11 (I); n = 11, 9, 9 (J); and n = 12, 10, 9 (K). All data are represented as mean ± SEM. P < 0.05 by 1-way ANOVA with Bonferroni’s corrections for multiple comparisons. Dapa, dapagliflozin; Tx, treatment; po, orally.