GPR119 expression in normal human tissues and islet cell tumors: evidence for its islet-gastrointestinal distribution, expression in pancreatic beta and alpha cells, and involvement in islet function

doi:10.1016/j.metabol.2012.06.010

Metabolism

Volume 62, Issue 1, January 2013, Pages 70-78

https://doi.org/10.1016/j.metabol.2012.06.010 Get rights and content

Abstract

Objective

GPR119 is reportedly involved in regulating glucose metabolism and food intake in rodents, but little is known about its expression and functional significance in humans. To begin to assess the potential clinical importance of GPR119, the distribution of GPR119 gene expression in humans was examined.

Materials/Methods

Expression of GPR119 mRNA in fresh samples of normal human pancreas (n = 19) and pancreatic islets (n = 3) and in insulinomas (n = 2) and glucagonomas (n = 2), all collected at surgery, was compared with the mRNA expression of various receptors highly expressed and operative in human pancreatic islets.

Results

GPR119 mRNA was most abundant in the pancreas, followed by the duodenum, stomach, jejunum, ileum and colon. Pancreatic levels of GPR119 mRNA were similar to those of GPR40 mRNA and were higher than those of GLP1R and SUR1 mRNA, which are strongly expressed in human pancreatic islets. Moreover, levels of GPR119 mRNA in pancreatic islets were more than 10 times higher than in adjacent pancreatic tissue, as were levels of GPR40 mRNA. GPR119 mRNA was also abundant in two cases of insulinoma and two cases of glucagonoma, but was undetectable in a pancreatic acinar cell tumor. Similar results were obtained with mouse pancreatic islets, MIN6 insulinoma cells and alpha-TC glucagonoma cells.

Conclusions

The results provide evidence of an islet-gastrointestinal distribution of GPR119, its expression in pancreatic beta and alpha cells, and its possible involvement in islet function. They also provide the basis for a better understanding of the potential clinical importance of GPR119.

Introduction

Endogenous lipids such as free fatty acids and acylethanolamides are known to regulate glucose metabolism and food intake [1], [2], [3]. The underlying molecular mechanisms are not fully understood, however. Recently, four orphan G protein-coupled receptors (GPR40, GPR41, GPR43 and GPR120) were deorphaned and identified as fatty acid receptors [4], [5], [6], [7], [8]. Among those, we found that GPR40 is highly expressed in human pancreatic beta cells and is involved in regulating insulin secretion [9], [10]. In addition, GPR119 has been identified as a Gs-coupled receptor whose putative endogenous ligands include oleoylethanolamide (OEA) [11], [12] and possibly other lipids [13], [14], [15], [16]. In vitro studies have implicated GPR119 in the regulation of insulin and incretin secretion [12], [14], [15], [17], [18], [19], [20], and in vivo studies in rats and mice suggest its involvement in the regulation of glucose metabolism and feeding [11], [14], [18], [19], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30]. That said, glucose metabolism in humans and mice may differ [31], and little is known about the expression and physiological significance of GPR119 in humans.

In that context, we examined GPR119 gene expression in various human tissues, including fresh samples of pancreas and digestive tract collected at surgery. In addition, to gain further insight into the localization of GPR119 within the human pancreas, we compared GPR119 expression in human pancreatic islets and adjacent pancreatic tissue, as well as in insulinomas and glucagonomas, two very rare human tumors that possess the endocrine properties of pancreatic beta and alpha cells, respectively. The results provide evidence of the islet-gastrointestinal distribution of GPR119, its expression in pancreatic beta and alpha cells, and its possible involvement in islet function in humans.

Section snippets

Subjects, tissue sampling and pancreatic islet isolation

The clinical profiles of all patients enrolled in the present study are shown in Table 1. The study was performed in accordance with the Declaration of Helsinki and approved by the Ethical Committee on Human Research of Kyoto University Graduate School of Medicine. Signed informed consent was obtained from all patients.

Normal human cerebral tissues (n = 3) were collected from three patients at autopsy; one had died from amyotrophic lateral sclerosis, one from an iliopsoas muscle tumor and one

Expression of GPR119 mRNA in normal human tissues

We initially tested for GPR119 mRNA in samples of commercially available total RNA from normal human tissues. We found that the transcript was most abundant in the pancreas, followed by the gastrointestinal tract (small intestine, colon and stomach) and the testis (Fig. 1A). GPR119 mRNA was not detected in any other human tissue tested. To gain further insight into GPR119 gene expression humans and verify the aforementioned distribution profile, we also examined tissues obtained at surgery or

Discussion

Our findings demonstrate for the first time that GPR119 is highly expressed in human pancreatic islets, where the level of GPR119 expression is enriched more than 10-fold, as compared to adjacent areas of the pancreas in the same individuals. We also found that pancreatic levels of GPR119 mRNA are similar to those of GPR40 mRNA and are higher than those of GLP1R and SUR1 mRNA. Likewise, the level of GPR119 mRNA in isolated pancreatic islets is similar to that of GPR40 mRNA and higher than those

Author contributions

SO: data collection and analysis, data interpretation, manuscript writing. KH: data interpretation, manuscript writing. TT: data analysis, data interpretation, manuscript writing. JF, TK and KE: data interpretation, manuscript writing. YK, RD, KT, YS and SU: data collection, data interpretation. KN: data interpretation, manuscript writing.

Funding

This work was supported in part by the Ministry of Education, Culture, Sports, Science and Technology of Japan; Ministry of Health, Labor and Welfare of Japan; Takeda Medical Research Foundation; Smoking Research Foundation; Suzuken Memorial Foundation; Japan Foundation of Applied Enzymology; Novo Nordisk Insulin Research award; and Lilly Education and Research Grant Office. We gratefully acknowledge cooperative research program FINDS with Shionogi & Co., Ltd.

Conflict of Interest

The authors have no conflict of interest to declare.

Acknowledgment

The authors acknowledge the technical assistance of Ms. A. Ryu of Kyoto University Graduate School of Medicine.

References (44)

A.J. Brown et al.
The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids
J Biol Chem
(2003)
T. Tomita et al.
GPR40 gene expression in human pancreas and insulinoma
Biochem Biophys Res Commun
(2005)
H.A. Overton et al.
Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents
Cell Metab
(2006)
T. Soga et al.
Lysophosphatidylcholine enhances glucose-dependent insulin secretion via an orphan G-protein-coupled receptor
Biochem Biophys Res Commun
(2005)
R. Kogure et al.
5-Hydroxy-eicosapentaenoic acid is an endogenous GPR119 agonist and enhances glucose-dependent insulin secretion
Biochem Biophys Res Commun
(2011)
J. Gao et al.
Stimulating beta-cell replication and improving islet graft function by AR231453, A gpr119 agonist
Transplant Proc
(2011)
G. Semple et al.
Discovery of fused bicyclic agonists of the orphan G-protein coupled receptor GPR119 with in vivo activity in rodent models of glucose control
Bioorg Med Chem Lett
(2011)
H.M. Cox et al.
Peptide YY is critical for acylethanolamine receptor Gpr119-induced activation of gastrointestinal mucosal responses
Cell Metab
(2010)
H. Iwakura et al.
Analysis of rat insulin II promoter-ghrelin transgenic mice and rat glucagon promoter-ghrelin transgenic mice
J Biol Chem
(2005)
C.P. Briscoe et al.
The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids
J Biol Chem
(2003)

A.S. Rajan et al.

Sulfonylurea receptors and ATP-sensitive K + channels in clonal pancreatic alpha cells. Evidence for two high affinity sulfonylurea receptors

J Biol Chem

(1993)

G.J. Dockray

The versatility of the vagus

Physiol Behav

(2009)

M.S. Engelstoft et al.

A gut feeling for obesity: 7TM sensors on enteroendocrine cells

Cell Metab

(2008)

D.T. Stein et al.

The insulinotropic potency of fatty acids is influenced profoundly by their chain length and degree of saturation

J Clin Invest

(1997)

T.K. Lam et al.

Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis

Nat Med

(2005)

J. Fu et al.

Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha

Nature

(2003)

Y. Itoh et al.

Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40

Nature

(2003)

A. Hirasawa et al.

Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120

Nat Med

(2005)

B. Ahren

Islet G protein-coupled receptors as potential targets for treatment of type 2 diabetes

Nat Rev Drug Discov

(2009)

M.A. Kebede et al.

Lipid receptors and islet function: therapeutic implications?

Diabetes Obes Metab

(2009)

T. Tomita et al.

Expression of the gene for a membrane-bound fatty acid receptor in the pancreas and islet cell tumours in humans: evidence for GPR40 expression in pancreatic beta cells and implications for insulin secretion

Diabetologia

(2006)

L.M. Lauffer et al.

GPR119 is essential for oleoylethanolamide-induced glucagon-like peptide-1 secretion from the intestinal enteroendocrine L-cell

Diabetes

(2009)

Cited by (51)

G protein-coupled receptors driven intestinal glucagon-like peptide-1 reprogramming for obesity: Hope or hype?
2024, Biomedicine and Pharmacotherapy
‘Globesity’ is a foremost challenge to the healthcare system. The limited efficacy and adverse effects of available oral pharmacotherapies pose a significant obstacle in the fight against obesity. The biology of the leading incretin hormone glucagon-like-peptide-1 (GLP-1) has been highly captivated during the last decade owing to its multisystemic pleiotropic clinical outcomes beyond inherent glucoregulatory action. That fostered a pharmaceutical interest in synthetic GLP-1 analogues to tackle type-2 diabetes (T2D), obesity and related complications. Besides, mechanistic insights on metabolic surgeries allude to an incretin-based hormonal combination strategy for weight loss that emerged as a forerunner for the discovery of injectable ‘unimolecular poly-incretin-agonist’ therapies. Physiologically, intestinal enteroendocrine L-cells (EECs) are the prominent endogenous source of GLP-1 peptide. Despite comprehending the potential of various G protein-coupled receptors (GPCRs) to stimulate endogenous GLP-1 secretion, decades of translational GPCR research have failed to yield regulatory-approved endogenous GLP-1 secretagogue oral therapy. Lately, a dual/poly-GPCR agonism strategy has emerged as an alternative approach to the traditional mono-GPCR concept. This review aims to gain a comprehensive understanding by revisiting the pharmacology of a few potential GPCR-based complementary avenues that have drawn attention to the design of orally active poly-GPCR agonist therapy. The merits, challenges and recent developments that may aid future poly-GPCR drug discovery are critically discussed. Subsequently, we project the mechanism-based therapeutic potential and limitations of oral poly-GPCR agonism strategy to augment intestinal GLP-1 for weight loss. We further extend our discussion to compare the poly-GPCR agonism approach over invasive surgical and injectable GLP-1-based regimens currently in clinical practice for obesity.
Intestinal GPR119 activation by microbiota-derived metabolites impacts feeding behavior and energy metabolism
2023, Molecular Metabolism
The gastrointestinal tract affects physiological activities and behavior by secreting hormones and generating signals through the activation of nutrient sensors. GPR119, a lipid sensor, is indirectly involved in the secretion of incretins, such as glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, by enteroendocrine cells, while it directly stimulates insulin secretion by pancreatic beta cells. Since GPR119 has the potential to modulate metabolic homeostasis in obesity and diabetes, it has attracted interest as a therapeutic target. However, previous studies have shown that the deletion of Gpr119 in mice does not affect glucose homeostasis and appetite in either basal or high-fat diet-fed conditions. Therefore, the present study aimed to explore the role of GPR119 signaling system in energy metabolism and feeding behavior in mice.
Gpr119 knockout (KO) mice were generated using CRISPR-Cas9 gene-editing technology, and their feeding behavior and energy metabolism were evaluated and compared with those of wild type (WT) mice.
Upon inducing metabolic stress via food deprivation, Gpr119 KO mice exhibited lower blood glucose levels and a higher body weight reduction compared to WT mice. Although food intake in WT and KO mice were similar under free-feeding conditions, Gpr119 KO mice exhibited increased food intake when they were refed after 24 h of food deprivation. Further, food-deprived Gpr119 KO mice presented shorter post-meal intervals and lower satiety for second and later meals during refeeding, resulting in increased food intake. Associated with this meal pattern, levels of oleoylethanolamide (OEA), an endogenous agonist of GPR119, in the luminal contents of the distal gastrointestinal tract were elevated within 2 h after refeeding. The large-intestinal infusion of OEA prolonged post-meal intervals and increased satiety in the first meal, but not the second meal. On the other hand, infusion of oleic acid increased cecal OEA levels at 2 h from the beginning of infusion, while prolonging post-meal intervals and increasing satiety on the meals that occurred approximately 2 h after the infusion. Cecal OEA levels were low in antibiotic-treated mice, suggesting that the gut microbiota partially synthesizes OEA from oleic acid.
Collectively, our results indicate that the activation of gastrointestinal GPR119 by microbiota-produced OEA derived from oleic acid is associated with satiety control and energy homeostasis under energy shortage conditions.
Targeting Enteroendocrine Cells to Treat Metabolic Disease
2022, Comprehensive Pharmacology
Enteroendocrine cells are specialized hormone-producing cells located in the gastrointestinal epithelium. There are thought to be several different enteroendocrine cell types which modulate their release of specific hormones or combinations of hormones in response to stimuli, including the presence or absorption of specific macronutrient and metabolite molecules. These hormones then mediate a number of physiological processes, acting on the gastrointestinal tract to regulate activities including gut motility, absorption and secretion, and acting on other organs to influence glucose homeostasis and appetite.
The effects of gut hormones on glucose and energy homeostasis are of particular interest regarding their therapeutic potential to treat metabolic diseases such as obesity and type 2 diabetes. There are already drugs based on gut hormone systems, though they have limitations including unwanted pharmacological side effects. To date, agents designed to manipulate the release of the endogenous pool of gut hormones have not been used clinically, though some have been trialled for metabolic disease. This article discusses how enteroendocrine cells develop from stem cells in the gut, and the molecular machinery that mediates the effects of particular stimuli on gut hormone release from mature enteroendocrine cells. We consider how specific macronutrients, bacterial metabolites, bile acids and immune system mediators can modulate the release of gastrointestinal hormones, and whether these systems may be amenable to therapeutic exploitation.
GPR119 agonists: Novel therapeutic agents for type 2 diabetes mellitus
2021, Bioorganic Chemistry
Diabetes mellitus type 2 (T2D) is a group of genetically heterogeneous metabolic disorders whose frequency has gradually risen worldwide. Diabetes mellitus Type 2 (T2D) has started to achieve a pandemic level, and it is estimated that within the next decade, cases of diabetes might get double due to increase in aging population. Diabetes is rightly called the 'silent killer' because it has emerged to be one of the major causes, leading to renal failure, loss of vision; besides cardiac arrest in India. Thus, a clinical requirement for the oral drug molecules monitoring glucose homeostasis appears to be unmet. GPR119 agonist, a family of G-protein coupled receptors, usually noticed in β-cells of pancreatic as well as intestinal L cells, drew considerable interest for type 2 diabetes mellitus (T2D). GPR119 monitors physiological mechanisms that enhance homeostasis of glucose, such as glucose-like peptide-1, gastrointestinal incretin hormone levels, pancreatic beta cell-dependent insulin secretion and glucose-dependent insulinotropic peptide (GIP). In this manuscript, we have reviewed the work done in the last five years (2015–2020) which gives an approach to design, synthesize, evaluate and study the structural activity relationship of novel GPR119 agonist-based lead compounds. Our article would help the researchers and guide their endeavours in the direction of strategy and development of innovative, effective GPR119 agonist-based compounds for the management of diabetes mellitus type 2.
Targeting GPCRs Activated by Fatty Acid-Derived Lipids in Type 2 Diabetes
2019, Trends in Molecular Medicine
Citation Excerpt :
However, the discussion about the ‘true’ GPR119 endogenous ligands is ongoing due to their low potency and poor selectivity. GPR119 is predominantly expressed in the K and L cells of the intestinal tract, as well as α- and β-cells of pancreatic islets [60,61]. Activation of GPR119 is associated directly and indirectly with modulation of insulin secretion, as it stimulates insulin secretion from pancreatic β-cells, as well as GLP-1 and GIP from intestinal L and K cells, respectively [7,62,63].
G protein-coupled receptors (GPCRs) are the most intensively studied drug targets, because of their diversity, cell-specific expression, and druggable sites accessible at the cell surface. Preclinical and clinical studies suggest that targeting GPCRs activated by fatty acid-derived lipids may have potential to improve glucose homeostasis and reduce complications in patients with type 2 diabetes (T2D). Despite the discontinued development of fasiglifam (TAK-875), the first FFA1 agonist to reach late-stage clinical trials, lipid-sensing receptors remain a viable target, albeit with a need for further characterization of their binding mode, intracellular signaling, and toxicity. Herein, we analyze general discovery trends, various signaling pathways, as well as possible challenges following activation of GPCRs that have been validated clinically to control blood glucose levels.
Expression and distribution of GPR55 and GPR119 during the development of rat testis
2023, Ankara Universitesi Veteriner Fakultesi Dergisi

View all citing articles on Scopus

View full text

Basic ScienceGPR119 expression in normal human tissues and islet cell tumors: evidence for its islet-gastrointestinal distribution, expression in pancreatic beta and alpha cells, and involvement in islet function

Abstract

Objective

Materials/Methods

Results

Conclusions

Introduction

Section snippets

Subjects, tissue sampling and pancreatic islet isolation

Expression of GPR119 mRNA in normal human tissues

Discussion

Author contributions

Funding

Conflict of Interest

Acknowledgment

J Biol Chem

Biochem Biophys Res Commun

Cell Metab

Biochem Biophys Res Commun

Biochem Biophys Res Commun

Transplant Proc

Bioorg Med Chem Lett

Cell Metab

J Biol Chem

J Biol Chem

J Biol Chem

Physiol Behav

Cell Metab

The insulinotropic potency of fatty acids is influenced profoundly by their chain length and degree of saturation

J Clin Invest

Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis

Nat Med

Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha

Nature

Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40

Nature

Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120

Nat Med

Islet G protein-coupled receptors as potential targets for treatment of type 2 diabetes

Nat Rev Drug Discov

Lipid receptors and islet function: therapeutic implications?

Diabetes Obes Metab

Expression of the gene for a membrane-bound fatty acid receptor in the pancreas and islet cell tumours in humans: evidence for GPR40 expression in pancreatic beta cells and implications for insulin secretion

Diabetologia

GPR119 is essential for oleoylethanolamide-induced glucagon-like peptide-1 secretion from the intestinal enteroendocrine L-cell

Diabetes

Basic Science
GPR119 expression in normal human tissues and islet cell tumors: evidence for its islet-gastrointestinal distribution, expression in pancreatic beta and alpha cells, and involvement in islet function