Defining the long term pathophysiological determinants of type 2 diabetes

Abstract

The prevalence of type 2 diabetes has increased significantly worldwide in recent decades along with growing rates of obesity. This presents a huge challenge to the health care systems all over the globe as well as ill health in millions of individuals. Defining the long-term pathophysiological determinants of type 2 diabetes and the mechanisms underlying the normalisation of blood glucose levels have great implications for the effective management of early type 2 diabetes. The Twin Cycle hypothesis which explains the major pathophysiological changes in type 2 diabetes has been further validated in this work. This thesis presents metabolic and clinical data from Tyneside arm of Diabetes Remission Clinical Trial (DiRECT), unravelling the mechanisms behind the remission of type 2 diabetes in people with a known duration of the disease of less than 6 years. The main culprits for non-reversal of type 2 diabetes were the lack of substantial weight loss and longer diabetes duration. Over 24 months of successful weight maintenance period the sustained decrease in VLDL-TG production by liver was followed by a reduction in liver and pancreatic fat content, a rise in first phase insulin secretion, and a near normalisation of maximum insulin secretory capacity. These factors have permitted to keep the normal blood glucose control in participants who did not have major weight regain. A group of non-diabetic individuals were studies specifically to allow comparison with the Tyneside DiRECT cohort after weight loss to evaluate just how far the underlying pathophysiological processes returned towards normal. Weight loss induced decrease in liver enzymes levels reflected the reduction in liver fat content. The changes were analysed in detail. In routine clinical practice sequential monitoring of liver enzymes following weight loss can provide a simple assessment of normalisation of liver fat. In conclusion, a low-calorie diet intervention induced a durable remission in early type 2 for up to 24 months for most people who achieved substantial weight loss. Overall, the metabolic findings of this thesis provide clinically important insights into the pathophysiologic basis of remission of type 2 diabetes