title: The bile acid TUDCA increases glucose-induced insulin secretion via the cAMP/PKA pathway in pancreatic beta cells.
abstract: 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 β-cells.
  
  
  METHODS
  Pancreatic islets were isolated from 90-day-old male mice. Insulin secretion was measured by radioimmunoassay, protein phosphorylation by western blot, Ca(2+) signals by fluorescence microscopy and ATP-dependent K(+) (KATP) 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, Ca(2+) signals or KATP channel activity; however, it was lost in the presence of a cAMP competitor or a PKA inhibitor. Additionally, PKA and CREB phosphorylation were observed after 1-hour incubation with TUDCA. The potentiation of GSIS was blunted by the Gα stimulatory, G protein subunit-specific inhibitor NF449 and mimicked by the specific TGR5 agonist INT-777, pointing to the involvement of the bile acid G protein-coupled receptor TGR5.
  
  
  CONCLUSIONS
  Our data indicate that TUDCA potentiates GSIS through the cAMP/PKA pathway.
authors.affiliation: Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), 13083-970 Campinas, SP, Brazil; Institute of Bioengineering and the Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM), Miguel Hernández University, 03202, Elche, Spain.
authors.forename: Jean Franciesco
authors.initials: JF
authors.lastname: Vettorazzi
authors.affiliation: Integrated Laboratory of Morphology, Centre for Ecology and Socio-Environmental - NUPEM, Federal University of Rio de Janeiro (UFRJ), Macaé, Rio de Janeiro, Brazil.
authors.forename: Rosane Aparecida
authors.initials: RA
authors.lastname: Ribeiro
authors.affiliation: Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), 13083-970 Campinas, SP, Brazil.
authors.forename: Patricia Cristine
authors.initials: PC
authors.lastname: Borck
authors.affiliation: Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), 13083-970 Campinas, SP, Brazil.
authors.forename: Renato Chaves Souto
authors.initials: RC
authors.lastname: Branco
authors.affiliation: Department of Physiology, Genetics and Microbiology, University of Alicante, 03080 Alicante, Spain.
authors.forename: Sergi
authors.initials: S
authors.lastname: Soriano
authors.affiliation: Institute of Bioengineering and the Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM), Miguel Hernández University, 03202, Elche, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Merino
authors.affiliation: Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), 13083-970 Campinas, SP, Brazil.
authors.forename: Antônio Carlos
authors.initials: AC
authors.lastname: Boschero
authors.affiliation: Institute of Bioengineering and the Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM), Miguel Hernández University, 03202, Elche, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Nadal
authors.affiliation: Institute of Bioengineering and the Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM), Miguel Hernández University, 03202, Elche, Spain.
authors.forename: Ivan
authors.initials: I
authors.lastname: Quesada
authors.affiliation: Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), 13083-970 Campinas, SP, Brazil. Electronic address: emc@unicamp.br.
authors.forename: Everardo Magalhães
authors.initials: EM
authors.lastname: Carneiro
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D000242:Cyclic AMP / Q000502:physiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000494:pharmacology*; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D054086:KATP Channels / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C513561:Gpbar1 protein, mouse; D007328:Insulin; D054086:KATP Channels; D047428:Protein Kinase Inhibitors; D043562:Receptors, G-Protein-Coupled; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose
keywords: Bile acids; Insulin secretion; TUDCA; β-cell