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
| Autor: | Didier Bagnol, Dominic P. Behan, Hui Gao, James N. Leonard, Zhi-Liang Chu, Melinda Pedraza, Hongmei He, Jean Alfonso, Veronica Gutierrez, Ruoping Chen, Helen Mondala, Annette Lucman, Robert M. Jones, Chris Carroll |
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| Rok vydání: | 2008 |
| Předmět: |
Blood Glucose
Male medicine.medical_specialty Enteroendocrine Cells Incretin Enteroendocrine cell Gastric Inhibitory Polypeptide Biology Glucagon-Like Peptide-1 Receptor Receptors G-Protein-Coupled Mice Endocrinology Gastric inhibitory polypeptide Glucagon-Like Peptide 1 Internal medicine Insulin-Secreting Cells medicine Cyclic AMP Receptors Glucagon Glucose homeostasis Animals Humans Tissue Distribution RNA Messenger Receptor Cells Cultured Mice Knockout Dipeptidyl-Peptidase IV Inhibitors Oxadiazoles digestive oral and skin physiology Glucagon-like peptide-1 Mice Inbred C57BL GPR119 Pyrimidines Glycemic Index Intestinal L Cells |
| Zdroj: | Endocrinology. 149(5) |
| ISSN: | 0013-7227 |
| Popis: | 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 β-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 β-cells. These data also suggest that combined stimulation of incretin hormone release and protection against incretin hormone degradation may be an effective antidiabetic strategy. |
| Databáze: | OpenAIRE |
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