胆汁酸牛磺熊去氧胆酸（TUDCA）通过环磷酸腺苷/蛋白激酶A（cAMP/PKA）信号通路增加胰腺β细胞中葡萄糖诱导的胰岛素分泌。
The bile acid TUDCA increases glucose-induced insulin secretion via the cAMP/PKA pathway in pancreatic beta cells.
作者信息
Vettorazzi Jean Franciesco, Ribeiro Rosane Aparecida, Borck Patricia Cristine, Branco Renato Chaves Souto, Soriano Sergi, Merino Beatriz, Boschero Antônio Carlos, Nadal Angel, Quesada Ivan, Carneiro Everardo Magalhães
机构信息
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.
Integrated Laboratory of Morphology, Centre for Ecology and Socio-Environmental - NUPEM, Federal University of Rio de Janeiro (UFRJ), Macaé, Rio de Janeiro, Brazil.
出版信息
Metabolism. 2016 Mar;65(3):54-63. doi: 10.1016/j.metabol.2015.10.021. Epub 2015 Oct 17.
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.
CONCLUSION
Our data indicate that TUDCA potentiates GSIS through the cAMP/PKA pathway.
目的
胆汁酸对消化过程很重要，同时它们在包括内分泌胰腺在内的许多组织中也作为信号分子发挥作用，内分泌胰腺表达特定的胆汁酸受体，这些受体调节多种细胞功能。在本研究中，我们研究了结合型胆汁酸牛磺熊去氧胆酸（TUDCA）对胰腺β细胞葡萄糖刺激的胰岛素分泌（GSIS）的影响。
方法
从90日龄雄性小鼠分离胰岛。通过放射免疫测定法测量胰岛素分泌，通过蛋白质印迹法检测蛋白质磷酸化，通过荧光显微镜检测Ca(2+)信号，通过电生理学检测ATP依赖性钾（KATP）通道。
结果
在刺激葡萄糖浓度下，TUDCA剂量依赖性地增加新鲜胰岛中的GSIS，但在低葡萄糖水平时无作用。这种作用与葡萄糖代谢、Ca(2+)信号或KATP通道活性的变化无关；然而，在存在cAMP竞争剂或PKA抑制剂的情况下这种作用消失。此外，与TUDCA孵育1小时后观察到PKA和CREB磷酸化。GSIS的增强作用被Gα刺激性G蛋白亚基特异性抑制剂NF449减弱，并被特异性TGR5激动剂INT-777模拟，表明胆汁酸G蛋白偶联受体TGR5参与其中。
结论
我们的数据表明，TUDCA通过cAMP/PKA途径增强GSIS。
Zotero 插件