Unravelling the pathogenesis of type 2 diabetes

PhD ThesisType 2 diabetes has become a worldwide epidemic. It is characterised by insulin resistance in major metabolic tissues, and failure of -pancreatic cells to compensate for this abnormality. Insulin resistance is recognised as an early event in the pathogenesis of type 2 diabetes. Although the precise factors that lead to insulin resistance have not been elucidated fully, there is strong association between insulin resistance and lipid accumulation, in particular lipotoxic fatty acid metabolites in insulin-target tissues. Most recently, evidence has been presented to link abnormal fatty acid accumulation in muscle with reduced mitochondrial activity. However it was unclear if these aberrations are causally related to the development of insulin resistance and type 2 diabetes. The two major pathophysiological abnormalities that underlie type 2 diabetes have long been viewed to require two separate pathogenic processes. The resolution of type 2 diabetes after bariatric surgery has allowed the elucidation of the sequence of events that lead to the restoration of normal metabolism, paving the way for a new understanding of type 2 diabetes as a metabolic state precipitated by a single cause of chronic excess intra-organ lipid accumulation. Magnetic resonance technique provides a non-invasive way to evaluate metabolism in both normal and pathological states. Specifically, 31P magnetic resonance spectroscopy allows the observation of real-time ATP synthesis as a direct measurement of mitochondrial activity. 13C magnetic resonance spectroscopy can be applied to assess muscle glycogen concentration. Both 1H magnetic resonance spectroscopy and magnetic resonance imaging can be used to evaluate intra-organ lipid concentration. Collectively, these innovative techniques offer safe and powerful approaches to study the role of skeletal muscle oxidative capacity and intra-organ fatty acid accumulation and metabolism in the pathogenesis of type 2 diabetes. This thesis presents data which lead to a simplified understanding of the aetiology and pathogenesis of type 2 diabetes.The Wellcome Trust, Newcastle upon Tyne, MRC Biomedical Research Centre and Diabetes UK