Investigation of the Metabolic Effects of Liraglutide on Patients with Overweight and Obesity

PhD Thesis

Spencer, L. 2023. Investigation of the Metabolic Effects of Liraglutide on Patients with Overweight and Obesity. PhD Thesis
AuthorsSpencer, L.
TypePhD Thesis

Obesity is a well-established risk factor for type 2 diabetes (T2D), a chronic metabolic disorder affecting millions worldwide. While lifestyle interventions such as diet and exercise are often the first-line treatment for obesity and T2D, pharmacological interventions can also play a crucial role in managing these conditions. Liraglutide is a glucagon-like peptide-1 receptor agonist that has been approved for the treatment of obesity and T2D. It works by reducing appetite, promoting weight loss, and improving glycemic control. However, the precise mechanisms underlying the beneficial effects of liraglutide on metabolism and glucose homeostasis are not fully understood.

The aim of this study was to investigate the beneficial metabolic sequelae of Liraglutide in patients with obesity or overweight, including changes in vital signs, anthropometric characteristics (weight, body mass index, and body composition), biochemical parameters, metabolomics, and miRNA molecules from blood tests. The study hypothesis was that treatment with Liraglutide 3mg daily would have beneficial effects on patients with overweight or obesity.

Firstly, a systematic review was conducted to examine the current knowledge base of GLP-1 receptor agonist treatment, focusing on metabolic changes associated with the treatment. A 24-week open-label real-world study was conducted, including 62 participants. Once-daily subcutaneous liraglutide 3.0 mg was administered alongside a reduced calorie diet. The study assessed the primary outcome of body weight change, as well as secondary outcomes of changes in anthropometrics, proinflammatory cytokines, and plasma metabolome using UPLC-MS. Total RNA was extracted from adipocytes, and gene expression profiles were compared between liraglutide-treated and non-treated cells to examine changes in metabolic pathways. In addition, PE, PC, and S1P assays were conducted to analyze the lipid metabolism based on the findings from human samples. Furthermore, miRNA analysis was performed to explore the potential molecular mechanisms underlying the metabolic effects of liraglutide.

The results of the systematic review found that Liraglutide alters metabolic markers in patients with obesity and T2DM. However, further trials were needed to detect the mechanism of GLP-1RA action on molecular pathways and determine novel biomarkers of treatment effects. The clinical study found that liraglutide was associated with upregulation of S1P and reduction of IL-6 in super-responders, with mild to moderate nausea and diarrhea being the most frequently reported adverse events. Additionally, liraglutide treatment led to reduced body weight and improved metabolic control, similar to findings in regulatory trials. The study's results provide evidence of the beneficial effects of liraglutide on lipid metabolism, insulin sensitivity, and inflammation. They suggest that gene expression profiling and miRNA expression may be useful in predicting liraglutide treatment response and identifying novel therapeutic targets for diabetes and obesity. Further research is required to confirm these findings and determine the molecular mechanisms involved in liraglutide's effects on adipose tissue function. Of particular interest is the relationship between the findings of S1P, ceramide, SPHK1 and SPHK2, all of which are involved in the S1P signalling pathway, which could be an important regulator of metabolic and immune function.

KeywordsLiraglutide; overweight; obesity; type 2 diabetes; metabolomics
PublisherCollege of Science and Engineering, University of Derby
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Deposited22 Aug 2023
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