Gastrectomy, Eating Behaviour and GLP-1

The Effect of Glucagon Like Peptide-1 (GLP-1) on Glycaemic Profile and Eating Behaviour Following Gastrectomy

Patients who have undergone gastrectomy (removal of the stomach) to treat or prevent cancer are known to have a significantly reduced quality of life. To date, there is very little information on the physiological causes of this. The investigators suspect that overproduction of a hormone (chemical) called glucagon like peptide-1 (GLP-1) released by the lining of the gut may play a role in the reduced appetite, weight loss and low blood sugar symptoms seen in this group. To investigate this, the investigators will study the response of 16 patients who have previously had a gastrectomy to a glucose drink, and a meal, while receiving an infusion of a specific blocker of GLP-1 or placebo. The investigators will examine the levels of sugar and associated hormones in the blood, food consumption and food reward behaviour using standard tools. Participants will be invited to attend the Clinical Research Facility at Addenbrooke's Hospital for a screening visit, and two whole day study visits. The study has been designed to assess the role of overproduction of GLP-1 by completely blocking its actions, rather than assess the use of the blocking compound as a medication, and is therefore regarded as a physiological study, not a clinical trial. The goal of this study is to demonstrate the magnitude of effect of GLP-1 on blood sugar and appetite derangement in patients who have had a gastrectomy. This will guide future work on the development of novel treatment paradigms for the post-gastrectomy patient group.

Complete blockade of action of endogenous GLP-1 by Exendin 9-39. Defined as a physiological study, not a clinical trial as such (as advised by the UK MHRA).

Lowest blood sugar reading during an oral glucose tolerance test while receiving infusion of GLP-1 antagonist. Please note participants will receive infusion of active compound for a maximum of four hours, with no expected effect of compound persisting for more than 30 minutes post-infusion.

As assessed during a 50g glucose tolerance test while receiving infusion of GLP-1 antagonist. At time 30-120 minutes of infusion of Exendin 9-39.

60 minute incremental area under the curve (i.e. total) insulin secretion during 50g oral glucose tolerance test while receiving infusion of GLP-1 antagonist. Please note participants will receive infusion of active compound for a maximum of four hours, with no expected effect of compound persisting for more than 30 minutes post-infusion.

As measured by universal eating monitor, total weight of a standardised meal consumed over a measured time in grams per minute.

Will be measured on visual analogue scale and reported as a score out of 100. Higher value indicated more hunger and more satiety.

150-240 minutes during infusion of Exendin 9-39 or placebo and for 4 hours post-cessation of infusion.

Food motivation can be measured by response rates to visual cues while being distracted by food related images. Will be measured with and without GLP-1 blockade to investigate effects of GLP-1 on food attention behaviour. Measure is of difference in response time when visual cue is colocated with a food related image vs a non-food related image, indicating degree of bias in attention to food images. Measure is undertaken during infusion at four timepoints - baseline (i.e. fasting), post oral glucose tolerance test (post-OGTT), before a standard meal (pre-meal) and after the meal (post-meal).

0-240 minutes during infusion of Exendin 9-39 or placebo, assessed on four occasions (baseline or T0, post-OGTT, pre-meal, post-meal) using a validated dot-probe visual response tool and reported in response time (milliseconds).

Participant motivation to view particular food based cues is assessed by grip strength exerted to maintain those cues. Measure is undertaken during infusion at four timepoints - baseline (i.e. fasting), post oral glucose tolerance test (post-OGTT), before a standard meal (pre-meal) and after the meal (post-meal).

0-240 minutes during infusion of Exendin 9-39 or placebo (baseline or T0, post-OGTT, pre-m, assessed on four occasions using a validated grip strength surrogate of food motivation and measured as the area under the curve of a grip force monitoring curve.

Total consumption amount of a standard meal during study intervention, measured in grams using a universal eating monitor.

Inclusion Criteria: • At least 3 months post completion of treatment for gastric cancer, or prophylactic gastrectomy Aged at least 18 years Able to tolerate an oral glucose tolerance test Able to understand and retain all information regarding the study and give informed consent. Willing to receive an infusion of human albumin solution Exclusion Criteria: • Have a diagnosis of diabetes Have a history of untreated anaemia in the last 3 months Be aged under 18 years Have active gastric cancer Be pregnant or attempting to conceive