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      GPR119 Is Essential for Oleoylethanolamide-Induced Glucagon-Like Peptide-1 Secretion From the Intestinal Enteroendocrine L-Cell

      1 , 1 , 1 , 2


      American Diabetes Association

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          Intestinal L-cells secrete the incretin glucagon-like peptide-1 (GLP-1) in response to ingestion of nutrients, especially long-chain fatty acids. The Gαs-coupled receptor GPR119 binds the long-chain fatty acid derivate oleoylethanolamide (OEA), and GPR119 agonists enhance GLP-1 secretion. We therefore hypothesized that OEA stimulates GLP-1 release through a GPR119-dependent mechanism.


          Murine (m) GLUTag, human (h) NCI-H716, and primary fetal rat intestinal L-cell models were used for RT-PCR and for cAMP and GLP-1 radioimmunoassay. Anesthetized rats received intravenous or intraileal OEA, and plasma bioactive GLP-1, insulin, and glucose levels were determined by enzyme-linked immunosorbent assay or glucose analyzer.


          GPR119 messenger RNA was detected in all L-cell models. OEA treatment (10 μmol/l) of mGLUTag cells increased cAMP levels ( P < 0.05) and GLP-1 secretion ( P < 0.001) in all models, with desensitization of the secretory response at higher concentrations. GLP-1 secretion was further enhanced by prevention of OEA degradation using the fatty acid amide hydrolase inhibitor, URB597 ( P < 0.05–0.001 vs. OEA alone), and was abolished by H89-induced inhibition of protein kinase A. OEA-induced cAMP levels and GLP-1 secretion were significantly reduced in mGLUTag cells transfected with GPR119-specific small interfering RNA ( P < 0.05). Application of OEA (10 μmol/l) directly into the rat ileum, but not intravenously, increased plasma bioactive GLP-1 levels in euglycemic animals by 1.5-fold ( P < 0.05) and insulin levels by 3.9-fold ( P < 0.01) but only in the presence of hyperglycemia.


          The results of these studies demonstrate, for the first time, that OEA increases GLP-1 secretion from intestinal L-cells through activation of the novel GPR119 fatty acid derivate receptor in vitro and in vivo.

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          Most cited references 40

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          The biology of incretin hormones.

          Gut peptides, exemplified by glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted in a nutrient-dependent manner and stimulate glucose-dependent insulin secretion. Both GIP and GLP-1 also promote beta cell proliferation and inhibit apoptosis, leading to expansion of beta cell mass. GLP-1, but not GIP, controls glycemia via additional actions on glucose sensors, inhibition of gastric emptying, food intake and glucagon secretion. Furthermore, GLP-1, unlike GIP, potently stimulates insulin secretion and reduces blood glucose in human subjects with type 2 diabetes. This article summarizes current concepts of incretin action and highlights the potential therapeutic utility of GLP-1 receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors for the treatment of type 2 diabetes.
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            Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides.

            Endogenous neuromodulatory molecules are commonly coupled to specific metabolic enzymes to ensure rapid signal inactivation. Thus, acetylcholine is hydrolysed by acetylcholine esterase and tryptamine neurotransmitters like serotonin are degraded by monoamine oxidases. Previously, we reported the structure and sleep-inducing properties of cis-9-octadecenamide, a lipid isolated from the cerebrospinal fluid of sleep-deprived cats. cis-9-Octadecenamide, or oleamide, has since been shown to affect serotonergic systems and block gap-junction communication in glial cells (our unpublished results). We also identified a membrane-bound enzyme activity that hydrolyses oleamide to its inactive acid, oleic acid. We now report the mechanism-based isolation, cloning and expression of this enzyme activity, originally named oleamide hydrolase, from rat liver plasma membranes. We also show that oleamide hydrolase converts anandamide, a fatty-acid amide identified as the endogenous ligand for the cannabinoid receptor, to arachidonic acid, indicating that oleamide hydrolase may serve as the general inactivating enzyme for a growing family of bioactive signalling molecules, the fatty-acid amides. Therefore we will hereafter refer to oleamide hydrolase as fatty-acid amide hydrolase, in recognition of the plurality of fatty-acid amides that the enzyme can accept as substrates.
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              Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways.

              The glucagon-like peptide 1 receptor (GLP-1R) is believed to mediate glucoregulatory and cardiovascular effects of the incretin hormone GLP-1(7-36) (GLP-1), which is rapidly degraded by dipeptidyl peptidase-4 (DPP-4) to GLP-1(9-36), a truncated metabolite generally thought to be inactive. Novel drugs for the treatment of diabetes include analogues of GLP-1 and inhibitors of DPP-4; however, the cardiovascular effects of distinct GLP-1 peptides have received limited attention. Here, we show that endothelium and cardiac and vascular myocytes express a functional GLP-1R as GLP-1 administration increased glucose uptake, cAMP and cGMP release, left ventricular developed pressure, and coronary flow in isolated mouse hearts. GLP-1 also increased functional recovery and cardiomyocyte viability after ischemia-reperfusion injury of isolated hearts and dilated preconstricted arteries from wild-type mice. Unexpectedly, many of these actions of GLP-1 were preserved in Glp1r(-/-) mice. Furthermore, GLP-1(9-36) administration during reperfusion reduced ischemic damage after ischemia-reperfusion and increased cGMP release, vasodilatation, and coronary flow in wild-type and Glp1r(-/-) mice, with modest effects on glucose uptake. Studies using a DPP-4-resistant GLP-1R agonist and inhibitors of DPP-4 and nitric oxide synthase showed that the effects of GLP-1(7-36) were partly mediated by GLP-1(9-36) through a nitric oxide synthase-requiring mechanism that is independent of the known GLP-1R. These data describe cardioprotective actions of GLP-1(7-36) mediated through the known GLP-1R and novel cardiac and vascular actions of GLP-1(7-36) and its metabolite GLP-1(9-36) independent of the known GLP-1R. Our data suggest that the extent to which GLP-1 is metabolized to GLP-1(9-36) may have functional implications in the cardiovascular system.

                Author and article information

                American Diabetes Association
                May 2009
                17 February 2009
                : 58
                : 5
                : 1058-1066
                1Department of Physiology, University of Toronto, Toronto, Ontario, Canada; and the
                2Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
                Author notes
                Corresponding author: Patricia L. Brubaker, p.brubaker@ .
                © 2009 by the American Diabetes Association.

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                Original Article

                Endocrinology & Diabetes


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