The bile acid TUDCA increases glucose-induced insulin secretion via the cAMP/PKA pathway in pancreatic beta cells

Objective. While bile acids are important for the digestion process, they also act as signaling molecules in many tissues, including the endocrine pancreas, which expresses specific bile acid receptors that regulate several cell functions. In this study, we investigated the effects of the conjugated bile acid TUDCA on glucose-stimulated insulin secretion (GSIS) from pancreatic beta-cells. Methods. Pancreatic islets were isolated from 90-day-old male mice. Insulin secretion was, measured by radioimmunoassay, protein phosphorylation by western blot, Ca2+ signals by fluorescence microscopy and ATP-dependent K+ (K-ATP) channels by electrophysiology. Results. TUDCA dose-dependently increased GSIS in fresh islets at stimulatory glucose concentrations but remained without effect at low glucose levels. This effect was not associated with changes in glucose metabolism, Ca2+ signals or K-ATP channel activity; however, it was lost in the presence of a cAMP competitor or a PICA inhibitor. Additionally, PKA and CREB phosphorylation were observed after 1-hour incubation with TUDCA. The potentiation of GSIS was blunted by the G alpha stimulatory, G protein subunit-specific inhibitor NF449 and mimicked by the specific TGRS agonist INT-777, pointing to the involvement of the bile acid G protein-coupled receptor TGRS. Conclusion. Our data indicate that TUDCA potentiates GSIS through the cAMP/PKA pathway. (C) 2015 Elsevier Inc. All rights reserved.