Award Title: Are gut hormone changes why the long-limb gastric bypass is more effective than the standard-limb gastric bypass in improving type 2 diabetes mellitus? Extended Follow-up
Funder: Medical Research Council

Abstract: Obesity is the main cause of the world wide epidemic of diabetes. Weight loss, or ‘bariatric’, surgery produces major and sustained weight loss and is being increasingly used to treat obese diabetic patients. There was initial optimism that these procedures might “cure all diabetes”. However, the gold-standard operation, standard gastric bypass, effectively cures diabetes in only 4 out of 10 patients._x000D_
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To design a safer and more successful procedure we need to understand how bariatric surgery works to improve diabetes. Hormones from the gut are released when we eat food. They control how the body uses the food it absorbs. For example they release the sugar-lowering hormone insulin, and also greatly reduce appetite, which is why one feels less hungry after eating a meal. We have discovered that the good effects of bariatric surgery, and in particular the gastric bypass, are mainly due to increased release of gut hormones, reducing patient’s appetite and improving the release of insulin._x000D_
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In this project we will be testing a new procedure called the long-limb gastric bypass. It is designed particularly to be better at helping the diabetes in overweight patients, while being as safe as the currently available standard gastric bypass. We now want to show that this new procedure works better than the standard gastric bypass by causing an even bigger increase in the release of gut hormones and thus of insulin. We will take advantage of the fact that we already have a study, funded by the MRC, which examines the direct effect of gut hormones on appetite and insulin release. Using a newly developed technique (mass spectroscopy) we will measure the differences in gut hormone secretion between the new long-limb procedure and the standard gastric bypass far more accurately. In addition we will use a well-tested insulin sensitivity procedure (‘glucose clamp’), both to confirm and to investigate how and why the diabetes is so improved. The measurements we will be making are non-invasive and safe. The only discomfort comes from inserting a cannula to take blood samples._x000D_
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Patients who undergo this long-limb gastric bypass procedure should have fewer complications from diabetes, use fewer medications, and have better overall health and quality of life. If we can show that the benefit of the new modified procedure is indeed due to the increased release of gut hormones and insulin, this may lead to improvements in the design of surgical procedures, will better enable us to offer the right patient the right procedure, and will form the basis for designing improved drug treatments for diabetes.

Lay Abstract: This proposal builds on the MRC grant, MR/K02115X/1, which identifies the importance of enhanced gut hormone release in mediating the weight loss and improvement in carbohydrate metabolism after standard-limb Roux-en-Y gastric bypass surgery (RYGB)._x000D_
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The laparoscopic standard-limb RYGB procedure is the “gold-standard” bariatric surgery procedure because of its superior risk/benefit profile. Standard-limb RYGB involves the formation of a small gastric pouch, the formation of a gastric remnant and a biliopancreatic limb which are bypassed by nutrients. Type 2 diabetes mellitus (T2DM) patients after standard-limb RYGB lose ~30% of their body weight. Despite initial optimism that this operation would cause long term remission for the majority of patients with moderate diabetes, disappointingly, <40% achieve euglycaemia without diabetic medications (Brethauer SA et al, Ann Surg 2013)._x000D_
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We, and others, have shown that standard-limb RYGB improves glucose control by increasing the immediate post-prandial release of insulin and reducing insulin resistance (Dirksen C et al, Diabetologia 2012). The faster delivery of nutrients to the distal intestine, where gut neuroendocrine L cells are located, stimulates the release of gut hormones (GLP-1, oxyntomodulin, PYY) which suppress appetite and enhance insulin release. These are thought, but not yet conclusively proven, to mediate the enhanced immediate insulin secretion after standard-limb RYGB. We know it is possible to obtain even greater improvement in glycaemic control than standard-limb RYGB by using a longer intestinal bypass, which will further enhance gut hormone release, insulin release, and sensitivity to insulin._x000D_
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Long biliopancreatic limb, or long-limb, RYGB is thus a new procedure which produces a greater enhancement of glucose tolerance. Thus a stratified approach may be preferable for treating obese patients with T2DM with more critical impairments of glucose control (Nora et al, Obes Surg 2011). Long-limb RYGB is designed to place nutrients further down the small intestine thus avoiding the severe nutritional complications of older procedures, such as biliopancreatic diversion, whilst more strongly enhancing the release of gut hormones. In matched new cohorts of obese T2DM patients undergoing standard-limb and long-limb RYGB patients we will 1) measure the concentrations of gut hormones after both procedures using the new more specific and accurate technique of mass spectroscopy; 2) measure carbohydrate metabolism using an euglycaemic clamp procedure with isotopic markers; and 3) measure bile acid levels and the gut microbiome, parameters that may contribute to the improved outcome. The gut hormone dose response data established in the existing grant will provide a direct comparator to determine whether the increased gut hormone release expected after long-limb RYGB can explain the greater improvement of glucose tolerance. Identification or refutation of this mechanism as a major contributor to outcome is essential for rational design of these increasingly performed surgical procedures, will inform therapeutic decisions and will aid in future drug development._x000D_
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Within a 42 month period we will provide both mechanistic and clinical evidence to support the use of long-limb RYGB, a procedure that may be more effective in improving diabetes than standard-limb RYGB, and provide the rational basis for a stratified approach in bariatric surgery.

Research Activity Codes: 5.4 SURGERY;6.4 SURGERY
Health Categories: CANCER AND NEOPLASMS;CARDIOVASCULAR;METABOLIC AND ENDOCRINE;ORAL AND GASTROINTESTINAL;STROKE