Activation of Transmembrane Bile Acid Receptor TGR5 Modulates Pancreatic Islet α Cells to Promote Glucose Homeostasis

Jan 14, 2016The Journal of biological chemistry

Activation of a bile acid sensor in pancreas cells helps regulate blood sugar

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Abstract

TGR5 activation in pancreatic α cells may enhance GLP-1 release and improve insulin function.

Activation of TGR5 in pancreatic α cells leads to a shift from glucagon to GLP-1 synthesis in response to hyperglycemia.
This shift is mediated by a specific signaling pathway involving cAMP and a protein known as PC1.
Release of GLP-1 from α cells occurs through a mechanism that does not rely on PKA.
Administration of the TGR5 agonist, INT-777, resulted in reduced body weight and improved glucose tolerance in db/db mice.
INT-777 increased PC1 expression and stimulated GLP-1 release from islets in db/db mice compared to controls.
The GLP-1 receptor antagonist blocked the insulin release effect associated with TGR5-mediated GLP-1 from α cells.

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The physiological role of the TGR5 receptor in the pancreas is not fully understood. We previously showed that activation of 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 derived from alternate splicing of a common precursor, proglucagon by PC2 and PC1, respectively. We investigated whether TGR5 activation in pancreatic α cells enhances hyperglycemia-induced PC1 expression thereby releasing GLP-1, which in turn increases β cell mass and function in a paracrine manner. TGR5 activation augmented a hyperglycemia-induced switch from glucagon to GLP-1 synthesis in human and mouse islet α cells by GS/cAMP/PKA/cAMP-response element-binding protein-dependent activation of PC1. Furthermore, TGR5-induced GLP-1 release from α cells was via an Epac-mediated PKA-independent mechanism. Administration of the TGR5 agonist, INT-777, to db/db mice attenuated the increase in body weight and improved glucose tolerance and insulin sensitivity. INT-777 augmented PC1 expression in α cells and stimulated GLP-1 release from islets of db/db mice compared with control. INT-777 also increased pancreatic β cell proliferation and insulin synthesis. The effect of TGR5-mediated GLP-1 from α cells on insulin release from islets could be blocked by GLP-1 receptor antagonist. These results suggest that TGR5 activation mediates cross-talk between α and β cells by switching from glucagon to GLP-1 to restore β cell mass and function under hyperglycemic conditions. Thus, INT-777-mediated TGR5 activation could be leveraged as a novel way to treat type 2 diabetes mellitus.

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Activation of Transmembrane Bile Acid Receptor TGR5 Modulates Pancreatic Islet α Cells to Promote Glucose Homeostasis

Abstract

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