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Regulation of pancreatic β cell function by GLP‐1 released from α cells in response to activation of TGR5 by bile acids
Author(s) -
Kumar Divya,
Asgharpour Amon,
Mirshahi Fariddodin,
Grider John,
Murthy Karnam,
Sanyal Arun
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.lb656
Subject(s) - g protein coupled bile acid receptor , proglucagon , medicine , endocrinology , paracrine signalling , glucagon , pancreatic islets , insulin , glucagon like peptide 1 , bile acid , islet , secretion , receptor , gastric inhibitory polypeptide , biology , chemistry , diabetes mellitus , type 2 diabetes
We previously showed that activation of G s ‐coupled TGR5 in pancreatic β cells by bile acids induces insulin secretion. Glucagon released from pancreatic α cells and glucagon‐like peptide 1 (GLP‐1) released from intestinal L cells regulate insulin secretion. Both glucagon and GLP‐1 are processed from the same precursor, proglucagon by cell‐specific expression of proconvertases 1 (PC1) and PC2. AIM To test the hypothesis that TGR5 activation upregulates PC1 expression and GLP‐1 release from α cells and promotes insulin release in a paracrine fashion. RESULTS Expression of TGR5 was demonstrated in αTC1‐6 cells and islets from mouse and human. Treatment of αTC1‐6 cells, and islets from mice or human with 25 mM glucose for 7 days induced PC1 expression and GLP‐1 release; the effect of glucose was augmented by lithocholic acid and the TGR5 specific ligand, INT‐777. Insulin secretion by INT‐777 in human islets cultured under 25 mM glucose was inhibited by the GLP‐1 receptor antagonist, exendin (9‐39), suggesting augmentation of β cell function by GLP‐1 released from α cells. Treatment of islets from db/db mice, but not control mice with INT‐777 induced GLP‐1 release. Intraperitoneal treatment with INT‐777 for 7 weeks significantly attenuated the increase in body weight, and improved glucose tolerance and insulin sensitivity in db/db mice compared to control mice. CONCLUSION. Activation of TGR5 by bile acids augments hyperglycemia‐induced PC1 expression and GLP‐1 release in pancreatic α cells, which in turn, acts in a paracrine manner to promote insulin secretion from β cells. Thus, in diabetes, secretions of α and β cells act in concert to regulate blood glucose levels.