A Role for Intestinal Endocrine Cell-Expressed G Protein-Coupled Receptor 119 in Glycemic Control by Enhancing Glucagon-Like Peptide-1 and Glucose-Dependent Insulinotropic Peptide Release

Abstract

We recently showed that activation of G protein-coupled receptor 119 (GPR119) (also termed glucose dependent insulinotropic receptor) improves glucose homeostasis via direct cAMP-mediated enhancement of glucose-dependent insulin release in pancreatic beta-cells. Here we show that GPR119 also stimulates incretin hormone release and thus may regulate glucose homeostasis by this additional mechanism. GPR119 mRNA was found to be expressed at significant levels in intestinal subregions that produce glucose-dependent insulinotropic peptide and glucagon-like peptide (GLP)-1. Furthermore, in situ hybridization studies indicated that most GLP-1-producing cells coexpress GPR119 mRNA. In GLUTag cells, a well-established model of intestinal L-cell function, the potent GPR119 agonist AR231453 stimulated cAMP accumulation and GLP-1 release. When administered in mice, AR231453 increased active GLP-1 levels within 2 min after oral glucose delivery and substantially enhanced total glucose-dependent insulinotropic peptide levels. Blockade of GLP-1 receptor signaling with exendin(9-39) reduced the ability of AR231453 to improve glucose tolerance in mice. Conversely, combined administration of AR231453 and the DPP-4 inhibitor sitagliptin to wild-type mice significantly amplified both plasma GLP-1 levels and oral glucose tolerance, relative to either agent alone. In mice lacking GPR119, no such enhancement was seen. Thus, GPR119 regulates glucose tolerance by acting on intestinal endocrine cells as well as pancreatic beta-cells. These data also suggest that combined stimulation of incretin hormone release and protection against incretin hormone degradation may be an effective antidiabetic strategy.

Effect of the artificial sweetener, sucralose, on gastric emptying and incretin hormone release in healthy subjects

“…For example, GPR40 and GPR119 are both GPCR that may stimulate incretin release in response to fatty acids, and agonists of these receptors could be therapeutically useful in diabetes (8). Furthermore, sweet taste sensors other than T1R2, such as SGLT3 (11), could be important in the detecting carbohydrate in the small intestine.…”

G-protein coupled receptors mediating long chain fatty acid signalling in the pancreatic beta-cell

“…In order to evaluate this idea more fully, the distribution of GPR119 expression was examined in mammalian tissues by a number of authors and it was rapidly established that both the endocrine pancreas and certain cells of the GI tract express the receptor [87][88][89][90][91][92]. It is also possible that GPR119 may be expressed in some brain regions [93].…”

“…Ectopic expression of GPR119 in various easily transfected cell lines has yielded unanimous support for the view that activation of the receptor is associated with a rise in cAMP levels [101][102][103][104]. Moeover, exposure of cultured β-cells to GPR119 ligands also elicits a rise in cAMP; as does treatment of the intestinal Lcell line, GLUTag [105]. Thus, it can be concluded that GPR119 is predominantly coupled to Gs and that activation of the receptor promotes a rise in intracellular cAMP.…”

Fatty Acid Binding Receptors and Their Physiological Role in Type 2 Diabetes

“…The GPR119 agonist AR231453 exhibited good oral bioavailability properties and a dose of 20 mg/kg markedly improved oral glucose tolerance in a dose-dependent fashion [34]. Recently, Chu et al [35], demonstrated that AR231453 activating GPR119, stimulates GLP secretion providing an additional mechanism by which GPR119 regulates glucose homeostasis. The role of insulin release and GLP secretion by Arena compound AR231453 reportedly resulted in improved glucose tolerance, reduced body weight gain, and improved food intake.…”

“…No incretin effect was observed in GPR119 deficient mice. Co-adminstration of AR231453 and sitagliptin, a dipeptidyl peptidase-IV (DPP-4) inhibitor significantly amplified GLP-1 levels and improved glucose tolerance in wild-type mice compared to administration of either compound alone [35]. The combined effects of insulin release improved glucose tolerance, incretin, and hypophagic effects, makes GPR119 an attractive target for pharmacological intervention in treatment of type 2 diabetes and obesity [34].…”