1758-P: Biased GPBAR Signaling in Regulating Islet Homeostasis and Glucose Metabolism

Introduction & Objective: The bile acid membrane receptor GPBAR is an important drug development target for metabolic diseases. Previous studies have demonstrated that some bile acids and their analogues improve glucose metabolism homeostasis by activating GPBAR in vivo.

Results: We found that, in contrast to the endogenous ligand LCA, INT-777 exhibited a Gs-preference while P395 and OA exhibited a β-arrestin-2-bias. In the study, we selected natural product oleanolic acid (OA), bile acid analogue INT-777, endogenous bile acid and small molecule Gpbar agonist P395 to evaluate their effects in islets and found that INT-777 and P395 promoted glucose-stimulated insulin secretion at lower concentrations in pancreatic islets, while natural multiple bile acids as well as OA increased insulin secretion stimulated by high glucose only at high concentrations, as evidenced by Gpbar^-/- mice. In an immune factor-induced islet inflammation model, low concentrations of INT-777 and P395 were shown to exert anti-inflammatory effects, while natural bile acids and OA required high concentrations to exhibit similar effects. Moreover, the ligands that displayed an obvious for Gs signaling, INT-777 and LCA could significantly inhibit the endoplasmic reticulum stress induced by thapsigargin, but P395 did not, which were evidenced by pdx1-cre^+/-Gs^fl/fl mice and Arrb2^-/- mice.

Conclusion: These findings collectively indicated that ligands of GPBAR with Gs-biased viability, may could better improve islet homeostasis and provide a rational design of GPBAR-targeting drugs for diabetes or other metabolic diseases.