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

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• 作者：Jean Franciesco Vettorazzi^a ; ^d ; Rosane Aparecida Ribeiro^b ; Patricia Cristine Borck^a ; Renato Chaves Souto Branco^a ; Sergi Soriano^c ; Beatriz Merino^d ; Antô ; nio Carlos Boschero^a ; Angel Nadal^d ; Ivan Quesada^d ; ¹ ; Everardo Magalhã ; es Carneiro^a ; ¹ ; ^{emc@unicamp.br" class="auth_mail" title="E-mail the corresponding author}
• 关键词：6E-CDCA ; 6-Ethyl-chedeoxycholic acid ; ADP ; Adenosine diphosphate ; AKT or PTB ; Protein kinase B ; ATP ; Adenosine triphosphate ; AUC ; Area under curve ; BSA ; Bovine serum albumin ; cAMP ; Cyclic adenosine monophosphate ; CREB ; cAMP response element-binding protein ; DZX ; Diazoxide ; FXR ; Farnesoid X receptor ; GAPDH ; Glyceraldehyde 3-phosphate dehydrogenase ; GLP-1 ; Glucagon-like peptide 1 ; GLUT-2 ; Glucose transporter 2 ; GSIS ; Glucose-stimulated insulin secretion ; H89 ; Protein kinase A inhibitor ; INT-777 ; 6
• 刊名：Metabolism
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：65
• 期：3
• 页码：54-63
• 全文大小：844 K

文摘

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⁺ (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, Ca^2 + signals or K_ATP 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.

Conclusion

Our data indicate that TUDCA potentiates GSIS through the cAMP/PKA pathway.