Mechanisms By Which Glucose Lowering Therapies Reduce Obesity And Atherosclerosis

Abstract

The incidence of obesity, type 2 diabetes and cardiovascular disease (CVD) is increasing at alarming rates worldwide. Obesity is associated with a chronic nutrient surplus that contributes to chronic low-grade inflammation, ectopic lipid deposition and insulin resistance. Insulin resistance is an important factor contributing to the development of both type 2 diabetes and CVD. Therefore, therapies that can address multiple aspects of cardio-metabolic diseases could have significant clinical utility to reduce morbidity and mortality associated with these conditions. Several distinct glucose lowering therapies have been developed, targeting unique molecular targets. Interestingly, three district glucose lowering therapies, metformin, canagliflozin and salsalate have been shown to potently activate the central energy regulating enzyme, AMP activated protein kinase (AMPK). Activation of AMPK has been shown to be important for regulating fatty acid and cholesterol synthesis, fatty acid oxidation, glucose homeostasis, inflammation and whole-body energy expenditure. Therefore, the objective of this thesis was to examine the effects of metformin, canagliflozin and salsalate, on obesity, atherosclerosis, hepatic lipid metabolism, and macrophage inflammatory signalling and to delineate the mechanism(s) by which these changes occur. In this thesis we show that metformin reduces obesity through a circulating hormone GDF15, and that AMPK is not required for metformin induced GDF15 secretion. Additionally, we show that canagliflozin reduces hepatic cholesterol synthesis and macrophage IL1-1β secretion through mechanisms requiring AMPKβ1. Lastly, we show that salsalate reduces atherosclerosis in a manner dependent on macrophage AMPK β1 and this is associated with reduced macrophage proliferation in vitro and in vivo. These insights into the mechanisms by which these glucose lowering therapies elicit beneficial effects on obesity and atherosclerosis further our understanding of the potential use of these agents for treatments beyond improved glycemic control. Furthermore, this evidence can direct future drug development or drug combinations to more effectively treat multiple aspects of these common chronic diseases that affect over a billion people worldwide.