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The GLP-1 Receptor Agonist Liraglutide Increases Myocardial Glucose Oxidation Rates via Indirect Mechanisms and
Malak Almutairi1, Keshav Gopal1, Amanda A Greenwell1
1Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada; Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada.
Background:
Type 2 diabetes (T2D) increases risk for cardiovascular disease. Of interest, liraglutide, a therapy for T2D that activates the glucagon-like peptide-1 receptor to augment insulin secretion, reduces cardiovascular-related death in people with T2D, though it remains unknown how liraglutide produces these actions. Notably, the glucagon-like peptide-1 receptor is not expressed in ventricular cardiac myocytes, making it likely that ventricular myocardium-independent actions are involved. We hypothesized that augmented insulin secretion may explain how liraglutide indirectly mediates cardioprotection, which thereby increases myocardial glucose oxidation.
Methods:
C57BL/6J male mice were fed either a low-fat diet (lean) or were subjected to experimental T2D and treated with either saline or liraglutide 3× over a 24-hour period. Mice were subsequently euthanized and had their hearts perfused in the working mode to assess energy metabolism. A separate cohort of mice with T2D were treated with either vehicle control or liraglutide for 2 weeks for the assessment of cardiac function via ultrasound echocardiography.
Results:
Treatment of lean mice with liraglutide increased myocardial glucose oxidation without affecting glycolysis. Conversely, direct treatment of the isolated working heart with liraglutide had no effect on glucose oxidation. These findings were recapitulated in mice with T2D and associated with increased circulating insulin levels. Furthermore, liraglutide treatment alleviated diastolic dysfunction in mice with T2D, which was associated with enhanced pyruvate dehydrogenase activity, the rate-limiting enzyme of glucose oxidation.
Conclusions:
Our data demonstrate that liraglutide augments myocardial glucose oxidation via indirect mechanisms, which may contribute to how liraglutide improves cardiovascular outcomes in people with T2D.
Insights
Liraglutide enhances heart glucose utilization indirectly, improving cardiovascular outcomes in type 2 diabetes. This occurs through increased insulin secretion, not direct heart effects, alleviating diastolic dysfunction.
Area of Science:
- Cardiology
- Endocrinology
- Metabolism
Background:
- Type 2 diabetes (T2D) significantly elevates cardiovascular disease (CVD) risk.
- Liraglutide, a T2D therapy, activates the glucagon-like peptide-1 receptor, enhancing insulin secretion and reducing CVD mortality.
- The mechanism behind liraglutide's cardioprotective effects is unclear, as the glucagon-like peptide-1 receptor is not expressed in ventricular cardiac myocytes, suggesting indirect actions.
Purpose of the Study:
- To investigate the indirect mechanisms by which liraglutide mediates cardioprotection in type 2 diabetes.
- To determine if augmented insulin secretion contributes to liraglutide's beneficial effects on myocardial metabolism and cardiac function.
Main Methods:
- Male C57BL/6J mice with or without experimental T2D were treated with liraglutide or saline.
- Cardiac energy metabolism was assessed using working heart perfusions.
- Cardiac function was evaluated via ultrasound echocardiography in a separate cohort of T2D mice treated with liraglutide or vehicle control for two weeks.
Main Results:
- Liraglutide increased myocardial glucose oxidation in lean mice without altering glycolysis; direct cardiac treatment showed no effect.
- These effects were observed in T2D mice and correlated with elevated circulating insulin levels.
- Liraglutide treatment improved diastolic dysfunction in T2D mice, linked to enhanced pyruvate dehydrogenase activity, a key enzyme in glucose oxidation.
Conclusions:
- Liraglutide augments myocardial glucose oxidation through indirect mechanisms, likely involving increased insulin secretion.
- These indirect actions may play a significant role in liraglutide's observed cardiovascular benefits for patients with type 2 diabetes.
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