GLP-1R, a novel receptor in platelets, and the use of liraglutide in the treatment of obesity in women with PCOS

• Main Author: Kahal, Hassan
• Format: Dissertation
• Language: English
• Published: University of Hull and University of York 2013
• Subjects: Medicine

Studies investigating atherothrombotic risk in women with polycystic ovary syndrome (PCOS), in particular platelet function and carotid intima-media wall thickness (cIMT), have been confounded by not adequately accounting for obesity. Liraglutide is a glucagon like peptide-1 (GLP-1) analogue that causes weight loss and may have favourable effects on atherothrombotic risk and liver fibrosis in preclinical and animal studies. The aims of this study was to investigate whether atherothrombotic risk was increased in obese women with PCOS independently of obesity; whether GLP-1 receptor (GLP-1R) is expressed in human platelets; and whether 6 months treatment with liraglutide would improve weight and markers of atherothrombosis and liver fibrosis in obese young women with PCOS and/or normal controls. Our results suggest that PCOS, independent of obesity, is associated with increased levels of insulin resistance, inflammation, oxidative stress, non-alcoholic fatty liver disease (NAFLD) and the liver fibrosis marker PIIINP. However, PCOS was not independently associated with increased atherothrombotic risk markers including cIMT, platelet function, clot function/lysis, and endothelial function. Treatment for 6 months with liraglutide, 1.8mg daily, resulted in 3 – 4% weight loss in obese women with PCOS and controls. This was associated with a significant reduction in insulin resistance, oxidative stress, and several markers of atherothrombosis including inflammation, serum biochemical markers of endothelial function and clot lysis. Although basal platelet activation was reduced in the control group only and the liver fibrosis marker PIIINP was only reduced in the PCOS group, between groups comparisons were not significant. No change was observed in cIMT. In addition, we demonstrated for the first time that platelets express the GLP-1R. Liraglutide inhibited collagen- and thrombin-induced aggregation in isolated platelets and the effects were at least partly mediated by the GLP-1R, although an additional GLP-1R independent pathway is also likely. In conclusion, cardiovascular risk in young obese women with PCOS can either be attributed to obesity or is not yet apparent at this early stage of the condition. Our data support the use of liraglutide as a weight loss medication in simple obesity and suggest a potential beneficial effect on atherothrombotic risk and markers of liver fibrosis at 6 months of treatment. GLP-1R is a novel receptor in platelets and its function and clinical effect are worth further evaluation.