Do gut hormones mediate the beneficial effects of Roux-en-Y bypass surgery?

Obesity and diabetes are very common diseases which often go together. Over 1 in 4 people in the UK are obese. Together, these diseases afflict 300 million people and cause an estimated 3 million premature deaths a year. Surgery to reduce weight and especially the "Roux-en-Y gastric bypass" (RYGB) is known to reduce weight and to cure diabetes. Unfortunately surgery can never be the answer to the global problem of obesity and diabetes as it is very expensive, and can cause serious complications. We need a new, cheaper and adjustable treatment for obesity and diabetes that has the benefits of RYGB but without the side effects.

Gut hormones are hormones that the bowels make in response to eating. These hormones control our appetite and our metabolism (i.e. the method in which our body uses and stores food). The gut hormones glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM) and peptide YY (PYY) are much increased in level after RYGB. We believe that this increase in GLP-1, OXM and PYY holds the key to our goal to make a new treatment for obesity and diabetes. If we can prove that by artificially increasing GLP-1, OXM and PYY levels we can help obese diabetic patients to lose weight and to improve their blood sugar levels, this would be a breakthrough in treatment.

In this project, we aim to study obese, diabetic patients undergoing the RYGB surgery to see what changes occur in their gut hormone levels, in their metabolism, in their body weight and in their appetite for food. We will compare this to patients who will wear a 'pump' for 28 days. This pump will painlessly deliver a small amount of GLP-1, OXM and PYY via a soft plastic needle under the skin to raise their gut hormone levels. We will see if these pump patients have similar changes to the RYGB group. We will also test out a group of patients to see if similar changes occur when these patients are given a strict low-calorie diet. In this way we hope to understand whether we can make GLP-1, OXM and PYY into a new and better treatment for obesity and diabetes.

Obesity and the consequential type 2 diabetes (T2D) is the biggest pandemic the world has ever seen, afflicting 300 million people and causing an estimated 3 million premature deaths a year (WHO 2008). This is a considerable problem for public health and for therapeutics. The modern Roux-en-Y gastric bypass surgical procedure (RYGB) is highly effective in treating obesity and T2D: typically there is ~33% loss of body weight, producing complete remission of diabetes in about half the patients. Long term health and life expectation is dramatically increased. RYGB, however, is expensive, somewhat dangerous and is variable in effect. It is not desired by the majority of patients, nor is it practicable to treat the very large numbers of patients who might require it.

The challenge, therefore, is to demonstrate how RYGB works. This is the first step to identifying whether this could be translated into a practical, safe and titratable medical therapy for obesity and diabetes.

The remission of T2D and weight loss after RYGB has been attributed to a number of possible mechanisms, for example restriction of the stomach, interference with postprandial neural signals, delayed absorption of bile salts, delayed absorption of nutriments causing a change in breakdown of nutriments in the colon and / or an alteration of the gut microbiome. The evidence for each of these being the main cause of remission of diabetes is relatively weak. Outstandingly the likeliest mechanism proposed has been the elevation of gut hormones and enhancement thereby of the entero-insular axis.

Our previous work has shown gut hormones induce satiety, can enhance insulin release, and delay food absorption. They are elevated after RYGB. Evidence in animals suggests they might be the key mechanism producing the weight loss and improved carbohydrate tolerance in RYGB. We will establish in man whether this hypothesis is correct.

The ultimate beneficiaries of our research project will be patients with obesity and diabetes. As obesity is highly prevalent in the UK (25% of the population and rising) and worldwide, our research will clearly have a massive impact outwith the academic community. The following sections will discuss how we plan to maximize the impact of our research.

Application pathways
At the end of the project, we expect to have developed a proof-of-concept that GOP infusion is able to benefit patients with obesity and diabetes. This discovery could be exploited in two main ways:
1. Direct treatment with GLP-1, oxyntomodulin and PYY infusion pumps of patients with obesity and diabetes who are considered presently unsafe for surgery because of their extreme weight and/or uncontrolled diabetes. This would be envisaged as a 'bridge' towards eventual RYGB and similar surgery.
2. To spur the development and clinical use of analogues of GLP-1, oxyntomodulin and PYY as combination treatments for obesity and diabetes. Analogues of these gut hormones are currently in active development by our laboratory, other academic groups and the pharmaceutical industry, and the positive findings from our project would be expected to be directly and rapidly translatable to clinical practice.

The plan for application will be actively discussed and managed between the project team and the MRC.

Communications and engagement
Please see Communications Plan Section.

Resources requested
No extra resources for these impact activities are requested.