title: Ghrelin Is a Novel Regulator of GLP-1 Secretion.
abstract: GLP-1 is a gastrointestinal L-cell hormone that enhances glucose-stimulated insulin secretion. Hence, strategies that prevent GLP-1 degradation or activate the GLP-1 receptor are used to treat patients with type 2 diabetes. GLP-1 secretion occurs after a meal and is partly regulated by other circulating hormones. Ghrelin is a stomach-derived hormone that plays a key role in whole-body energy metabolism. Because ghrelin levels peak immediately before mealtimes, we hypothesized that ghrelin plays a role in priming the intestinal L-cell for nutrient-induced GLP-1 release. The intraperitoneal injection of ghrelin into mice 15 min before the administration of oral glucose enhanced glucose-stimulated GLP-1 release and improved glucose tolerance, whereas the ghrelin receptor antagonist D-Lys GHRP-6 reduced plasma levels of GLP-1 and insulin and diminished oral glucose tolerance. The ghrelin-mediated improvement in glucose tolerance was lost in mice coinjected with a GLP-1 receptor antagonist as well as in Glp1r(-/-) mice lacking the GLP-1 receptor. The impaired oral glucose tolerance in diet-induced obese mice was also improved by ghrelin preadministration. Importantly, ghrelin directly stimulated GLP-1 release from L-cell lines (murine GLUTag, human NCI-H716) through an extracellular signal-related kinase 1/2-dependent pathway. These studies demonstrate a novel role for ghrelin in enhancing the GLP-1 secretory response to ingested nutrients.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Gagnon
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada Lunenfeld-Tanenbaum Research Institute, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Laurie L
authors.initials: LL
authors.lastname: Baggio
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada Lunenfeld-Tanenbaum Research Institute, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada Department of Medicine, University of Toronto, Toronto, Ontario, Canada p.brubaker@utoronto.ca.
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Brubaker
mesh_terms: D000818:Animals; D002460:Cell Line; D054439:Ghrelin / Q000008:administration & dosage / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1 / Q000235:genetics / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D018149:Glucose Intolerance; D006706:Homeostasis; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018027:Receptors, Glucagon / Q000235:genetics / Q000378:metabolism*
chemical_list: C000593833:GLP1R protein, human; D054439:Ghrelin; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D018027:Receptors, Glucagon; D052216:Glucagon-Like Peptide 1; D005947:Glucose