GPBAR1 Agonism Improves Glucose Metabolism and Decreases Gallbladder Emptying in Mice
Abstract Number: 1003-P
Authors: JAMES HUBERT, ANDREA NAWROCKI, MARIA TRUJILLO, MARYANN POWLES, JAMES ORMES, RAVI KURUKULASURIYA, JAMES DELLUREFICIO, SHRENIK K. SHAH, SELENA FUNG, BOWEI WANG, JASON SZEWCZYK, RAVI P. NARGUND, DONALD J. MARSH, ROBERT J. DEVITA, ALESSANDRO POCAI
Institutions: Rahway, NJ
Results: Therapies that increase the circulating concentrations of insulin, like sulfonylureas and related insulin secretagogues, have proven beneficial in the treatment of T2D. DPP-4 inhibitors and peptidyl GLP-1 (glucagon-like peptide-1) mimetics represent new anti-diabetic agents that increase insulin secretion in a glucose-dependent manner, with little or no risk of hypoglycemia. GPBAR1 (G Protein Bile Acid Receptor 1) is a G protein-coupled receptor activated by hydrophobic bile acids and is expressed in enteroendocrine intestinal L cells, which secrete GLP-1. GPBAR1 activation promotes GLP-1 secretion in a murine enteroendocrine cell line. In this study, we examined whether acute administration of compound A, a small molecule GPBAR1 agonist, improves glucose metabolism in mice and if this effect is associated with changes in circulating GLP-1 levels. We also tested the effect of compound A on gallbladder emptying in mice since GPBAR1 activation has been linked to the disruption of gallbladder smooth muscle function.
Oral administration of compound A (mEC50= 25 nM) at 30 and 100 mg/kg led to an acute increase in plasma GLP-1 levels by 4- and 8-fold respectively vs. vehicle-treated mice. In addition, compound A, dosed 30 min before an oral glucose tolerance test (OGTT) led to a dose-dependent decrease in glucose excursion with complete suppression achieved at 30 mg/kg. Finally, compound A (30 mg/kg) and the positive control Devazepide (CCK-1 receptor antagonist) completely blocked both, CCK- and egg-yolk-induced gallbladder emptying.
In conclusion, small molecule GPBAR1 agonists represent a new class of GLP-1 secretagogues with potential for the management of diabetes. The effects of decreased gallbladder emptying by GPBAR1 and the potential to increase the risk of gallstone disease require further evaluation.