The ph.d. comprises of three studies:
1. To assess the effect of GLP-1 receptor agonist treatment on postprandial gallbladder emptying, liraglutide will be administered (3.0 mg once-daily) to overweight/obese subjects in a randomised, double-blinded, placebo-controlled parallel group trial.
2. Hormonal and other physiological parameters of potential importance for gallbladder motility and maximal ejection fraction and any liraglutide-mediated effect on gallbladder motility will also be alluded to; these include glucose-dependent insulinotropic polypeptide (GIP), CCK and the pancreatic hormones insulin, glucagon and pancreatic polypeptide (PP). The role of gallbladder emptying on the secretion of GLP-1, other gut hormones and the pancreatic hormones insulin and glucagon, and postprandial glucose metabolism will be examined in patients undergoing laparoscopic cholecystectomy.
3. Finally, detailed immunohistochemical analyses of the gallbladder and associated bile ducts (with focus on the existence and distribution of the GLP-1 receptor) will be performed.
Study 1 has already been carried out and study 2 and 3 are in progress.
What's to be investigated in the studies?
Study 2: The influence of cholecystectomy on secretion of incretin hormones
The effect of cholecystectomy on postprandial plasma GLP-1 responses (primary endpoint) and glucose metabolism will be evaluated in 30 patients planned to undergo elective laparoscopic cholecystectomy. Secondary endpoints include changes in plasma glucose, insulin, glucagon, GIP, PYY, gastrin, CCK, fibroblast growth factor 19 (FGF-19) and bile acids. Furthermore, secondary endpoints include changes in gastric emptying (evaluated by the paracetamol method). This is an observational, parallel-group study in 30 patients with gallstone disease and 10 healthy control subjects. In patients undergoing cholecystectomy a 4h-meal test (liquid mixed meal) will be conducted at baseline (1-2 weeks before surgery) and again within 4 weeks after the cholecystectomy. Healthy subjects will be submitted to a single 4h-meal test.
Study 3: Gut hormone receptors in the gallbladder
In order to test the molecular basis underlying the hypothesis that GLP-1 receptor agonists impair gallbladder motility through activation of GLP-1 receptors, immunohistochemical analyses of GLP-1 receptors will be performed on gallbladder biopsies obtained from patients included in Study 2. Activation of GLP-1 receptors on smooth muscle cells in the gallbladder could induce inhibitory effects on gallbladder contractility - directly or via paracrine effects (CCK, somatostatin, motilin). GLP-1 might also activate vagal afferents in the intestine that project to the CNS where vagal motor neurons become activated sending inhibitory impulses to the gallbladder. Also, stimulation of GLP-1 receptors may increase acetylcholine release from gallbladder neurons, as has been described following CCK-1 receptor activation. Therefore , immunohistochemical analyses of other gut hormone receptors as well as sympathetic and parasympathetic neurons - including myenteric neurons - will be performed.
Power analyses with a significance criterion of 0.05 and a power of >0.80 have been performed for all the studies in order to determine the necessary number of participants.
The project will entail a detailed examination of the role of gallbladder emptying for postprandial GLP-1 secretion. This will enhance our understanding of bile acid-induced GLP-1 secretion in human physiology. The project will add new knowledge to the exiting research field concerning pharmacologic targeting of TGR5 receptors for the treatment of obesity and type 2 diabetes and perhaps expose new treatment possibilities based on non-depositable GLP-1 secretagogues.
The three projects constituting the present PhD study will contribute to the unravelling of the interrelationship between gallbladder emptying and GLP-1 secretion
The immunohistochemical analyses will be performed in collaboration with Assoc. Prof. Steen S. Poulsen’s lab, University of Copenhagen, Denmark and Jens Pedersen, Jens J Holst lab at Panum, University of Copenhagen, Denmark
Bile acid profiles analysed by Matthew Gillum, Panum, University of Copenhagen, Denmark.
Incretin hormones analysed by Jens Juhl Holst, Panum, University of Copenhagen, Denmark.
Subjects will be recruited in collaboration with Søren Deigaard, surgical department, herlev/Gentofte Hospital, Helene Perregaard, surgical department, Hillerød hospital and Mikkel Westen, surgical department, Hvidovre hospital.