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Updated: Jun 5, 2025
Methods for the Determination of Rates of Glucose and Fatty Acid Oxidation in the Isolated Working Rat Heart
Published on: September 28, 2016
SGLT2 inhibition alters substrate utilization and mitochondrial redox in healthy and failing rat hearts
Leigh Goedeke1,2,3, Yina Ma4, Rafael C Gaspar1
1Department of Internal Medicine (Endocrinology), Yale School of Medicine, New Haven Connecticut, USA.
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.
Insights
Sodium-glucose cotransporter type 2 (SGLT2) inhibitors shift heart metabolism toward ketone use, distinct from ketone supplements. This metabolic shift may explain SGLT2 inhibitors' cardioprotective effects in heart failure.
Area of Science:
- Cardiovascular Metabolism
- Pharmacology
- Biochemistry
Background:
- Sodium-glucose cotransporter type 2 (SGLT2) inhibitors show cardioprotective potential in heart failure.
- SGLT2 inhibitors may protect the heart by increasing ketones and promoting their oxidation in the heart muscle.
- The distinct metabolic effects of SGLT2 inhibitors versus direct ketone supplementation are not fully understood.
Purpose of the Study:
- To investigate the differential effects of SGLT2 inhibition and ketone supplementation on cardiac metabolism.
- To elucidate the impact of SGLT2 inhibition on myocardial fuel utilization in both healthy and failing hearts.
Main Methods:
- Utilized gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS).
- Administered stable isotope tracers ([13C6]glucose or [13C4]βOHB) in awake rats.
- Induced heart failure to assess metabolic changes under disease conditions.
Main Results:
- Acute SGLT2 inhibition with dapagliflozin increased myocardial ketone oxidation and decreased pyruvate oxidation, independent of plasma glucose levels.
- Direct beta-hydroxybutyrate (βOHB) infusion increased ketone oxidation but reduced fatty acid oxidation without affecting glucose metabolism.
- In heart failure, dapagliflozin increased ketone and fatty acid oxidation while decreasing pyruvate oxidation, improving cardiac function and reducing oxidative stress.
Conclusions:
- SGLT2 inhibitors exert pleiotropic metabolic effects on the heart that are distinct from direct ketone supplementation.
- These unique metabolic alterations induced by SGLT2 inhibitors may contribute to their long-term cardioprotective benefits in heart failure.
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