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Endocrinology Vol. 149, No. 5 2035-2037
Copyright © 2008 by The Endocrine Society

GPR119: "Double-Dipping" for Better Glycemic Control

L. Lauffer, R. Iakoubov and P. L. Brubaker

Departments of Physiology (L.L., R.I., P.L.B.) and Medicine (P.L.B.) University of Toronto Toronto, Canada M5S 1A8

Address all correspondence and requests for reprints to: Patricia Brubaker, Ph.D., Department of Physiology, University of Toronto, Medical Science Building, Room 3366, 1 King’s College Circle, Toronto, Ontario, Canada M5S 1A8. E-mail: p.brubaker{at}utoronto.ca.

More than 100 yr have passed since Bayliss and Starling described the first intestinal hormone, secretin, with the following words: "contact ... with the epithelial cells ... causes in them the production of a body (secretin), which is absorbed from the cells by the blood-current and is carried to the pancreas, where it acts as a specific stimulus to the pancreatic cells, exciting secretion of pancreatic juice" (1). In 1932 Jean La Barré introduced the term incrétine (incretin) for substances derived from the upper intestine that exerted hypoglycemic effects (2). However, 5 additional decades were required before the two major incretin hormones were identified, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide (GLP)-1 (3, 4, 5). Since then, more than 2000 papers have been published describing the effects of GIP and GLP-1 as incretins. Why such interest? Produced by intestinal enteroendocrine cells in the upper and lower gut, respectively, GIP and GLP-1 appear to serve as endogenous antidiabetic hormones, stimulating glucose-dependent insulin secretion; GLP-1 additionally inhibits glucagon release, gastric emptying, and appetite (Fig. 1Go; for recent review see Ref. 6). However, whereas early experiments demonstrated that continuous infusion of GLP-1 into patients with type 2 diabetes mellitus (T2DM) improves glucose control (7), the actions of GIP appear to be blunted in such individuals (8). Furthermore, both of these hormones are rapidly degraded by the widely distributed enzyme, dipeptidylpeptidase-4 (DPP-4), thereby limiting their clinical relevance (9). Fortunately, a number of studies have demonstrated that chronic treatment with exenatide, a DPP-4-resistant GLP-1 receptor agonist, or liraglutide, a DPP-4-resistant GLP-1 analog, improves glycemic control and reduces hemoglobin A1c levels in patients with T2DM (10, 11, 12). A second approach by which incretin activity can be increased is provided by pharmacological inhibition of DPP-4 (e.g. with sitagliptin or vildagliptin), decreasing the degradation of GLP-1 and GIP and therefore prolonging their antidiabetic effects (12, 13, 14). Consistent with these demonstrated abilities to enhance incretin signaling, both exenatide and sitagliptin have recently been approved in North America and Europe for the treatment of patients with T2DM.


Figure 1
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  		FIG. 1. Luminal nutrients, particularly long-chain monounsaturated fatty acids, stimulate secretion of GLP-1 from the intestinal L-cell, leading to a variety of antidiabetic actions exerted through effects on multiple tissues. CNS, Central nervous system.

 
Another mechanism by which incretin effects could be enhanced therapeutically is via stimulation of the GLP-1-producing intestinal L-cells, localized at highest concentrations in the terminal ileum and colon in humans (15). Ingestion of carbohydrates and fat, especially long-chain monounsaturated fatty acids, stimulates GLP-1 release from the L-cell (for recent review, see Ref. 16). Although an attractive alternative to the use of incretin analogs or agonists and an approach that could be synergistic with DPP-4 inhibition, pharmacological stimulation of the L cell has not been possible to date due to a dearth of selective receptors. In this issue of Endocrinology, Chu et al. (17) report that the recently deorphanized G protein-coupled receptor, GPR119, is expressed on the L cell, and they show that stimulation with the pharmacological GPR119 agonist, AR231453, induces GLP-1 secretion from the L cell in enteroendocrine cell lines and enhances the release of both GLP-1 and GIP in vivo in mice.

A role for long-chain fatty acid-activated GPRs in the control of insulin secretion was first proposed with the discovery of GPR40 on the β-cell (18). This was rapidly followed by reports that the intestinal L cell also expresses GPR40 as well as another long-chain fatty acid receptor, GPR120, although the role of these proteins in the regulation of fat-induced GLP-1 secretion remains controversial (19, 20). A third long-chain fatty acid receptor, GPR119, was first deorphanized in 2005 by Soga et al. (21), and its expression in human pancreas and intestine was established shortly thereafter (22). Excitingly, an initial publication by Chu et al. (23) demonstrated that stimulation of pancreatic β-cells with a GPR119-selective agonist results in a marked enhancement of glucose-dependent insulin secretion. However, whereas GPR40 and GPR120 are G{alpha}q-coupled receptors, functioning through the inositol 1,4,5-triphosphate and Ca2+ pathway, GPR119 is coupled to G{alpha}s, causing activation of adenylyl cyclase and an increase in cAMP levels. The putative intracellular mechanisms underlying hormone secretion induced by these receptors are shown in Fig. 2Go.


Figure 2
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  		FIG. 2. Long-chain fatty acids enhance hormone secretion (e.g. insulin and GLP-1) through the newly deorphanized GPRs, GPR119, GPR40, and GPR120. The intracellular effects of these receptors are mediated through either cAMP- or phospholipase C (PLC)-dependent pathways. AC, Adenylyl cyclase; DAG, diacylglycerol; Epac, exchange protein activated by cAMP; IP3, inositol 1,4,5-trisphosphate; PIP2, phosphatidylinositol 4,5-bisphosphate; PK, protein kinase.

 
Unexpectedly, the first study on GPR119 by Chu et al. (23) also demonstrated that their GRP119 agonist had greater effects on insulin secretion when administered orally, compared with intravenously, suggesting an additional mechanism of action, such as modulation of the incretins. The main objective of the current study by Chu et al. (17) was therefore to examine the role of GPR119 in GLP-1 and GIP release. The authors detected GPR119 mRNA in mouse intestine as well as the mouse GLP-1-expressing intestinal cell lines, GLUTag and STC-1, by RT-PCR and Northern blot. In situ hybridization was also used to verify colocalization of GPR119 mRNA with proglucagon, the gene encoding GLP-1 in the intestinal L cell, although no expression could be detected in the GIP-producing K cell. Functional effects of the GPR119 receptor agonist, AR231453, were then demonstrated in vitro, through enhancement of both cAMP production and GLP-1 secretion by the GLUTag cells. Furthermore, AR231453 increased the secretion of GLP-1 and, somewhat surprisingly, GIP in vivo, in wild-type mice, but not in GPR119 null animals; a concomitant decrease in the glycemic response to an oral glucose load was also observed in the wild-type animals. Coadministration of the DPP-4 inhibitor, sitagliptin, to amplify the observed incretin effect, resulted in a further improvement in glycemic control in glucose-challenged animals. Most importantly, given the demonstrated effects of AR231453 to directly stimulate insulin secretion, its biological activity was diminished by approximately 50% when the GLP-1 receptor antagonist, exendin-49–39, was coadministered with the GPR119 agonist. Together, these findings suggest that approximately half of the effect of GPR119 agonism in vivo is mediated through the intestinal L cell, whereas the remaining effects are likely exerted through direct actions on the β-cell as well as, possibly, through indirect effects on GIP release. Nonetheless, whereas the distribution of GPR119 is established and some of its endogenous long-chain fatty acid ligands are known (21, 22), its actual physiological role remains completely unknown. Further studies are clearly necessary to address these questions as well as determine the role of GPR119 and the pharmacokinetics of AR231453 in humans.

Taken together, GPR119-specific agonists appear to provide a completely novel and previously unexplored approach to incretin therapy in patients with T2DM, increasing glucose-dependent insulin secretion through two complementary mechanisms: directly, through actions on the β-cell, and indirectly, through enhancement of GLP-1 and GIP release. Provided that such agents are well tolerated clinically, we are looking forward to this new and exciting dual approach to the treatment of diabetes.


   Footnotes
 
Work on glucagon-like peptide-1 in the Brubaker laboratory is supported by an operating grant from the Canadian Diabetes Association. L.L. is supported by an Albert Renold postdoctoral fellowship from the European Foundation for the Study of Diabetes, R.I. by postdoctoral fellowships from the Banting and Best Diabetes Centre, University of Toronto, and the German Research Foundation (Deutsche Forschungsgemeinschaft), and P.L.B. by the Canada Research Chairs program.

Disclosure Statement: L.L. and R.I. have nothing to declare. P.L.B. has served as consultant for Merck, Metabolex, and Johnson & Johnson and received lecture fees from GlaxoSmithKline.

See article p. 2038.

Abbreviations: DPP-4, Dipeptidylpeptidase-4; GIP, glucose-dependent insulinotropic peptide; GLP, glucagon-like peptide; GPR, G protein-coupled receptor; T2DM, type 2 diabetes mellitus.

Received February 7, 2008.

Accepted for publication February 11, 2008.


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