SGLT2 inhibition alters substrate utilization and mitochondrial redox in healthy and failing rat hearts
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
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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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 7

Chronic dapagliflozin treatment increases plasma

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Chronic dapagliflozin treatment increases plasma βOHB and improves LV ej...
βOHB and improves LV ejection fraction in rats 4 weeks after MI. (A) Outline of study design. Rats were given an intravenous bolus of 14C[2-DG] during the last 20 minutes of the infusion. (B–L) Body weight (B), plasma glucose (C), plasma glucagon (D), plasma insulin (E), plasma βOHB (F), plasma acetoacetate (G), plasma NEFAs (H), percentage change in heart rate (I), percentage change in diastolic volume (J), percentage change in stroke volume (K), and percentage change in LV ejection fraction (L) in chow-fed male rats 4 weeks after MI surgery and dapagliflozin (po) treatment (1.0 mg/kg body weight × 3 weeks). Panels B-H, were endpoint measures (4 weeks post-MI), while panels I-L represent percentage change from baseline (1 week post-MI compared with 4-weeks post-MI). In panels B–L, n = 15, 15 (B and I–L); n = 15, 13 (C); n = 11,10 (D); n = 9, 10 (E); n = 10, 8 (F); n = 10, 9 (G); and n = 11, 9 (H). All data are represented as mean ± SEM. P < 0.05 by unpaired Student’s t test.