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

Abstract

The physiological role of the TGR5 receptor in the pancreas is not fully understood. We previously showed that activation of TGR5 in pancreatic ␤ cells by bile acids induces insulin secretion. Glucagon released from pancreatic ␣ cells and glucagonlike 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 ␣ cells enhances hyperglycemia-induced PC1 expression thereby releasing GLP-1, which in turn increases ␤ cell mass and function in a paracrine manner. (11,12). Recently, TGR5 receptors have been identified on both pancreatic islet ␣ and ␤ cells (13,14). We have previously demonstrated that TGR5 activation on ␤ cells can increase insulin secretion (14). However, the function and physiological role of TGR5 in ␣ cells remain obscure.Glucagon and GLP-1 are produced from a common precursor proglucagon by alternate splicing mediated by proconvertase-2 (PC2) and PC1, respectively (15,16). Whereas the L cells express PC1 only, the pancreatic islet ␣ cells express both PC1 and PC2 (17). Under euglycemic conditions, PC2 activity predominates, and ␣ cells secrete mainly glucagon (18). We hypothesized that TGR5 activation by bile acids under hyperglycemia would activate PC1 as seen in L cells and switch the ␣ cell secretory phenotype from glucagon to GLP-1, which would have a trophic effect on adjacent ␤ cells in a paracrine manner. A combination of decreased systemic glucagon secretion and increased local GLP-1 production would be expected to improve insulin resistance and maintain islet ␤ cell mass. Indeed, several mouse models of diabetes such as streptozotocin-induced diabetes, prediabetic NOD mice, and both ob/ob and db/db mice are associated with increased ␣ cell PC1 and GLP-1 expression, although the mechanisms are not fully understood (19,20).

Bile acid metabolism and signaling in liver disease and therapy

“…Activation of TGR5 has been shown to protect against inflammation in the intestine and liver [50], stimulate GLP-1 secretion from enteroendocrine L cells and insulin synthesis and secretion from pancreatic β-cells [41, 75], and protect cholangiocytes from bile acid toxicity in cholestasis. Thus, it is a potential therapy for cholestasis [50].…”

TGR5, Not Only a Metabolic Regulator

“…As a result, TGR5 could be activated by WB403 to improve glucose tolerance, decrease fasting blood glucose and the glycosylated hemoglobin A1c (HbA1c) in T2D mice (Zheng et al, 2015). In the new reports, Kumar et al (2016) shown that TGR5 induced GLP-1 release from pancreatic α cells via an Epac-mediated PKA-independent mechanism. Agarwal et al (2016) also shown the important roles of TGR5 in T2D.…”

Bile acids and bariatric surgery

“…Li et al, 2011), modulates energy expenditure (Watanabe et al, 2006), stimulates GLP-1 release from intestinal L cells (Habib et al, 2013; Katsuma et al, 2005; Thomas et al, 2009), suppresses hepatic glycogenolysis (Potthoff et al, 2013) reduces inflammation (Frikke Schmidt et al, 2016) and inflammatory macrophage activation (Kawamata et al, 2003; Keitel et al, 2008; Lou et al, 2014; Maruyama et al, 2002; Y. D. Wang et al, 2008), improves pancreatic function (Kumar et al, 2016; Vettorazzi et al, 2016) and improves non-alcoholic fatty liver disease (Ding et al, 2016). TGR5 knockout mice have mildly reduced BA pools (Maruyama et al, 2006; Vassileva et al, 2006), impaired glucose tolerance (Thomas et al, 2009) and exacerbated inflammatory responses (Péan et al, 2013).…”