Roux-en-Y Gastric Bypass for obesity and type 2 diabetes: Clinical outcomes and mechanistic investigations

The prevalence of obesity is increasing at a rapid rate internationally, paralleled with an increase in the number of people with type 2 diabetes. Whilst the cornerstone of management of both conditions is lifestyle change, dietary interventions tend to result in only minimal weightless which is frequently regained over the subsequent years. Medical therapies for weight loss are only moderately more effective, whilst those used in the management of diabetes control hyperglycaemia rather than addressing the underlying pathophysiology. Bariatric surgery has therefore emerged as an apparently effective technique for both conditions, particular when occurring in association. Whilst high quality short term follow up studies now support bariatric surgery as the most effective treatment option available, there is a lack of longer term outcome studies to support its durability and safety. In chapter 1 of this thesis, I provide a summary of the current view of the pathophysiology of both obesity and type 2 diabetes, along with a review of non-surgical and surgical interventions. Lastly, I provide an overview of the research exploring the mechanisms by which bariatric surgery may induce these effects. In this thesis I report findings from a long term follow up study involving 118 participants following Roux-en-Y Gastric bypass surgery. The mean duration of follow up was 10.2 years, with the mean body weight loss 29.6% (38.5kg) at last follow up. 28% of participants with type 2 diabetes prior to surgery remained with type 2 diabetes at follow up, whilst 72% had improved glucose tolerance. Significant reductions in blood pressure and lipid markers were observed, as well as a reduced likelihood of depression, gout, and sleep apnoea after surgery. Quality of life was better when compared against non-surgical BMI matched controls. Furthermore, I report that the variable definitions of both diabetes at baseline and glycaemic outcomes used in the bariatric literature, results in significantly different published outcomes, and is an impediment to comparative analysis. In addition, I report the findings of two studies exploring further the mechanisms underlying the effects of bariatric surgery on durable weight loss and glucose homeostasis. In the first study, I demonstrate that whilst the acute hormonal stress response to RYGB surgery is short lived, an ongoing inflammatory response, still evident six days after surgery, should be considered when assessing changes in glucose homeostasis within this period. In the second study, I begin a line of research exploring the association between altered gut peptide physiology after bariatric surgery and longer term weight outcomes. These mechanistic studies are performed to both optimise outcomes following RYGB surgery, and to better understand the pathophysiology of obesity and type 2 diabetes