Journal Article

New Avenues in the Regulation of Gallbladder Motility—Implications for the Use of Glucagon-Like Peptide–Derived Drugs

Gether, Ida M, Knop, Filip K, Nexøe-Larsen, Christina

2019

Overview

Abstract Context Several cases of cholelithiasis and cholecystitis have been reported in patients treated with glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RAs) and GLP-2 receptor agonists (GLP-2RAs), respectively. Thus, the effects of GLP-1 and GLP-2 on gallbladder motility have been investigated. We have provided an overview of the mechanisms regulating gallbladder motility and highlight novel findings on the effects of bile acids and glucagon-like peptides on gallbladder motility. Evidence Acquisition The articles included in the present review were identified using electronic literature searches. The search results were narrowed to data reporting the effects of bile acids and GLPs on gallbladder motility. Evidence Synthesis Bile acids negate the effect of postprandial cholecystokinin-mediated gallbladder contraction. Two bile acid receptors seem to be involved in this feedback mechanism, the transmembrane Takeda G protein-coupled receptor 5 (TGR5) and the nuclear farnesoid X receptor. Furthermore, activation of TGR5 in enteroendocrine L cells leads to release of GLP-1 and, possibly, GLP-2. Recent findings have pointed to the existence of a bile acid–TGR5–L cell–GLP-2 axis that serves to terminate meal-induced gallbladder contraction and thereby initiate gallbladder refilling. GLP-2 might play a dominant role in this axis by directly relaxing the gallbladder. Moreover, recent findings have suggested GLP-1RA treatment prolongs the refilling phase of the gallbladder. Conclusions GLP-2 receptor activation in rodents acutely increases the volume of the gallbladder, which might explain the risk of gallbladder diseases associated with GLP-2RA treatment observed in humans. GLP-1RA-induced prolongation of human gallbladder refilling may explain the gallbladder events observed in GLP-1RA clinical trials. Recent studies have suggested that bile acids and GLP-2 terminate cholecystokinin-induced gallbladder contraction, and GLP-1 receptor agonist treatment decelerates gallbladder refilling.

• Publisher: Endocrine Society,Copyright Oxford University Press,Oxford University Press
• Subject: Acids / Agonists / Amino acids / Bile / Bile acids / Bile Acids and Salts - metabolism / Cholecystitis / Cholecystitis - chemically induced / Cholecystitis - physiopathology / Cholecystokinin / Cholecystokinin - metabolism / Cholelithiasis - chemically induced / Cholelithiasis - physiopathology / Clinical trials / Contraction / Deoxycholic acid / Diabetes Mellitus, Type 2 - drug therapy / G proteins / Gallbladder / Gallbladder - drug effects / Gallbladder - physiopathology / Gallbladder diseases / Gallbladder Emptying - drug effects / Gallbladder Emptying - physiology / GLP-1 receptor agonists / Glucagon / Glucagon-like peptide 1 / Glucagon-Like Peptide 1 - metabolism / Glucagon-Like Peptide 2 - metabolism / Glucagon-Like Peptide-1 Receptor - agonists / Glucagon-Like Peptide-1 Receptor - metabolism / Glucagon-Like Peptide-2 Receptor - agonists / Glucagon-Like Peptide-2 Receptor - metabolism / Glucagon-Like Peptides - adverse effects / Humans / L cells / Membrane proteins / Motility / Muscle Contraction - drug effects / Muscle Contraction - physiology / Muscle, Smooth - drug effects / Muscle, Smooth - physiopathology / Obesity - drug therapy / Peptides / Postprandial Period - physiology / Receptor mechanisms / Type 2 diabetes