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Cardioprotective effects of short-term empagliflozin treatment in db/db mice
Bernhard Radlinger1,2, Florian Hornsteiner1,2, Sabrina Folie1,2
1Department of Internal Medicine I, Christian Doppler Laboratory for Metabolic Crosstalk, Medical University Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria.
Abstract:
Sodium glucose transporter (SGLT)-2 inhibitors have consistently shown cardioprotective effects independent of the glycemic status of treated patients. In this study we aimed to investigate underlying mechanisms of short-term empagliflozin treatment in a mouse model of type II diabetes. Male db/db mice were fed a western type diet with or without enrichment with empagliflozin for 7 days. While glucose tolerance was significantly improved in empagliflozin treated mice, body weight and fasting insulin levels were comparable in both groups. Cardiac insulin signaling activity indicated by reduced proteinkinase B (AKT) phosphorylation was significantly decreased in the empagliflozin treated group. Remarkably, mitochondrial mass estimated by citrate synthase activity was significantly elevated in empagliflozin treated mice. Accordingly, mitochondrial morphology was significantly altered upon treatment with empagliflozin as analysed by transmission electron microscopy. Additionally, short-term empagliflozin therapy was associated with a changed cardiac tissue cytokine expression in favor of an anti-inflammatory pattern. Our data suggest that early cardioprotection in empagliflozin treated mice is independent of a reduction in body weight or hyperinsulinemia. Ameliorated mitochondrial ultrastructure, attenuated cardiac insulin signaling and diminished cardiac inflammation might contribute to the cardioprotective effects of empagliflozin.
Insights
Short-term empagliflozin improved glucose tolerance in diabetic mice without affecting weight or insulin. Early cardioprotection may stem from improved mitochondrial function and reduced cardiac inflammation.
Area of Science:
- Cardiology
- Endocrinology
- Pharmacology
Background:
- Sodium glucose transporter (SGLT)-2 inhibitors demonstrate cardioprotective effects irrespective of glycemic control.
- Understanding the mechanisms behind these effects is crucial for optimizing therapeutic strategies.
Purpose of the Study:
- To investigate the short-term mechanisms of empagliflozin's cardioprotective effects in a type II diabetes mouse model.
- To determine if these effects are independent of body weight and insulin levels.
Main Methods:
- Male db/db mice were treated with empagliflozin for 7 days.
- Assessed glucose tolerance, body weight, insulin levels, cardiac insulin signaling (AKT phosphorylation), mitochondrial mass (citrate synthase activity), mitochondrial morphology (TEM), and cardiac cytokine expression.
Main Results:
- Empagliflozin improved glucose tolerance but did not alter body weight or fasting insulin.
- Reduced cardiac AKT phosphorylation, increased mitochondrial mass and altered morphology were observed.
- A shift towards an anti-inflammatory cytokine profile in cardiac tissue was noted.
Conclusions:
- Short-term empagliflozin exerts cardioprotection in diabetic mice independent of weight loss or hyperinsulinemia.
- Improved mitochondrial ultrastructure, attenuated cardiac insulin signaling, and reduced cardiac inflammation likely contribute to these effects.
