Protective Effects and Mechanisms of Action of methyl-GBB in the Preclinical Models of Diabetes and Its Complications

The global prevalence of diabetes continues to rise concomitantly increasing the number of diabetes patients at risk of developing cardiovascular complications, such as atherosclerosis and ischaemic heart disease. Incomplete fatty acid oxidation and subsequent accumulation of fatty acid intermediates, long-chain acylcarnitines, are linked to the development of insulin resistance and cardiovascular diseases. Therefore, novel treatment strategies targeting fatty acid metabolism are needed to improve the clinical outcomes of patients with diabetes and its cardiovascular complications. The aim of the thesis was to investigate the pharmacological mechanisms of action of an acylcarnitine concentration lowering drug methyl-GBB in experimental animal models of diabetes, cardiac ischaemia/reperfusion injury and atherosclerosis. This thesis describes the molecular mechanisms of excessive accumulation of long-chain acylcarnitines and their detrimental effects during the development of insulin resistance and in the ischaemia/reperfusion-induced damage. The protective effects of lowering long-chain acylcarnitine levels by methyl-GBB treatment in experimental models of diabetes and atherosclerosis are described. The results indicate that accumulation of long-chain acylcarnitines limits metabolic flexibility and accelerates hyperglycaemia and hyperinsulinemia during the fed state. Methyl-GBB treatment-induced decrease in long-chain acylcarnitine content improves insulin sensitivity and significantly reduces blood glucose and insulin levels in mice with insulin resistance and diabetes. The results demonstrate that long-chain acylcarnitines are the main fatty acid intermediates that induce ischaemia/reperfusion-related damage by inhibiting oxidative phosphorylation and subsequent mitochondrial membrane hyperpolarization and stimulated production of reactive oxygen species in cardiac mitochondria. The anti-atherosclerotic effect of methyl-GBB treatment is mediated by decreased amounts of long-chain acylcarnitines and decreased infiltration of macrophages and monocytes into the aortic lesions of the aortic root. During this study, it was confirmed that pharmacologically induced decrease in the content of long-chain acylcarnitines by methyl-GBB facilitates glucose metabolism, improves insulin sensitivity, protects cardiac mitochondria against ischaemia/reperfusion injury and attenuates the development of atherosclerosis, and therefore represents an effective strategy for the treatment of diabetes and its complications.