Ghrelin Is a Novel Regulator of GLP-1 Secretion

Diabetes. 2015 May;64(5):1513-21. doi: 10.2337/db14-1176. Epub 2014 Nov 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Ghrelin / administration & dosage
  • Ghrelin / pharmacology*
  • Glucagon-Like Peptide 1 / genetics
  • Glucagon-Like Peptide 1 / metabolism*
  • Glucagon-Like Peptide-1 Receptor
  • Glucose / metabolism
  • Glucose / pharmacology
  • Glucose Intolerance
  • Homeostasis
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Glucagon / genetics
  • Receptors, Glucagon / metabolism*


  • GLP1R protein, human
  • Ghrelin
  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Receptors, Glucagon
  • Glucagon-Like Peptide 1
  • Glucose