The Metabolic Consequences of Gastrointestinal Surgery

The role of the gut hormone axis in glucose control is of significant interest due to its proven translational impact in diabetes management. It is also significantly altered by gastric surgery, a procedure that can lead to deleterious symptoms (dumping syndrome) in lean, non-diabetic patients. The investigators will study a unique cohort of young, lean patients undergoing surgery for the prevention of gastric cancer, as well as patients undergoing surgery for gastric and oesophageal cancer, to further understand the regulation and pathophysiological role of the gut hormone axis. The prophylactic patient population will be recruited from the pool of patients with a genetic mutation conferring a high lifetime risk of gastric cancer (Hereditary Diffuse Gastric Cancer) for whom Addenbrooke's Hospital provides a national clinical service. The investigators aim to define the causative physiological pathways for dumping syndrome in this group and expand our body of knowledge of gut hormones and their role in glucose homeostasis and eating behaviour.

It has been suspected for some years that surgery has more profound physiological effects than simple anatomical rearrangement, however recent developments in bariatric surgery have brought this to the fore. The era of surgical treatment of peptic ulcer disease resulted in a large cohort of patients undergoing gastric surgery and suffering post-operative dumping symptoms. These include symptoms attributed to hypovolaemia immediately after a meal, followed by hypoglycaemia within a few hours. There was a significant hiatus in the study of dumping syndrome after the decline of surgery for ulcer disease in the 1980s. The major improvement in long-term survival after surgery for oesophageal and gastric cancer seen in the 21st Century, coupled with the identification of high risk familial cohorts who now undergo prophylactic gastrectomy, has led to a growing cohort of long-term survivors after gastrectomy. This presents the significant challenge of defining and managing the ongoing, quality of life-limiting metabolic consequences of gastrointestinal surgery. The late dumping symptoms suffered by this patient cohort include paradoxical post-prandial hypoglycaemia, likely resulting from an excessive insulin response to particular components of ingested food.

There is also a population of patients undergoing oesophagectomy for malignant or pre-malignant conditions of the oesophagus, who receive post-operative nutrition through a feeding tube sited through the abdominal wall and entering the jejunum approximately 1 metre from its origin. This group of patients suffer similar metabolic changes to those undergoing gastrectomy, and provide a unique opportunity to study the differential response to nutrients administered orally or more distally. This could elucidate the role of any proximal gut hormones in glucose homeostasis.

The recent expansion in understanding of the metabolic effects of surgery has largely been driven by the study of bariatric (better termed metabolic) surgery. It is well known that Roux-en-Y gastric bypass (RYGB) can result in early remission of diabetes in 85% of cases and elevated levels of gut hormones such as glucagon-like peptide 1 (GLP-1), but there is considerable debate around whether the gut hormones changes contribute to the reductions in plasma glucose and appetite after surgery. Whereas studies in rodent models appear to indicate that gut hormones are largely redundant after bypass surgery, data from humans strongly support the idea that increased post-prandial GLP-1 and Peptide YY (PYY) levels underlie improvements in insulin secretion and reduced appetite. Studies from bariatric cohorts are confounded by the requirement for dietary restriction before surgery and massive weight loss after surgery.

Multiple studies have measured the baseline and stimulated levels of circulating gut hormones after RYGB in obese subjects. Elevated levels of GLP-1 and PYY and reduced levels of ghrelin have been reported in most studies, and variable results have been found for glucose-dependent insulinotropic peptide (GIP), cholecystokinin (CCK) and pancreatic polypeptide (PP).