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GLP-1R Agonists & Cardiac Energy Metabolism in Type 2 Diabetes
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- Author / Creator
- Almutairi,Malak
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Type 2 diabetes (T2D) is associated with an increased risk for cardiovascular disease. Of interest, liraglutide, a therapy for T2D that activates the glucagon-like peptide-1 receptor (GLP-1R) to augment insulin secretion, reduces cardiovascular-related death in people with T2D. However, it remains enigmatic as to how liraglutide may reduce cardiovascular death in patients with T2D. Importantly, the GLP-1R is not expressed in ventricular cardiac myocytes, so it is likely that indirect actions independent of the myocardium are involved. We hypothesized that augmented insulin secretion is a key factor contributing to liraglutide-induced cardioprotection, which thereby increases myocardial glucose oxidation. C57BL/6J male mice were fed either a low-fat diet for 10-weeks (lean) or were subjected to experimental T2D (10-weeks of high-fat diet supplementation plus a single injection of streptozotocin at 75 mg/kg 4-weeks into the protocol) and treated with either saline or liraglutide (30 g/kg via subcutaneous injection) 3x over a 24-hr period. 2-hr following the final injection, all mice were euthanized and had their hearts perfused in the working mode to assess myocardial energy metabolism. In a separate cohort of mice subjected to our experimental model of T2D, animals were randomized to receive either vehicle control or liraglutide treatment for 2-weeks, and cardiac function was assessed via ultrasound echocardiography prior to and upon completion of the study. Systemic treatment of lean mice with liraglutide increased myocardial glucose oxidation rates without affecting glycolysis rates. Conversely, direct treatment of the isolated working heart with liraglutide had no effect on glucose oxidation. These findings were recapitulated in mice with experimental T2D and associated with increased circulating insulin levels. Furthermore, Liraglutide treatment attenuated declining diastolic function in mice with experimental T2D. Our data demonstrates that liraglutide augments myocardial glucose oxidation via indirect mechanisms, which may mechanistically explain how liraglutide improves cardiovascular outcomes in people with T2D.
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- Subjects / Keywords
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- Graduation date
- Spring 2019
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- Type of Item
- Thesis
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- Degree
- Master of Science
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- License
- Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.