Pancreatic GLP-1 Receptor Activation Is Sufficient for Incretin Control of Glucose Metabolism in Mice

J Clin Invest. 2012 Jan;122(1):388-402. doi: 10.1172/JCI42497. Epub 2011 Dec 19.


Glucagon-like peptide-1 (GLP-1) circulates at low levels and acts as an incretin hormone, potentiating glucose-dependent insulin secretion from islet β cells. GLP-1 also modulates gastric emptying and engages neural circuits in the portal region and CNS that contribute to GLP-1 receptor-dependent (GLP-1R-dependent) regulation of glucose homeostasis. To elucidate the importance of pancreatic GLP-1R signaling for glucose homeostasis, we generated transgenic mice that expressed the human GLP-1R in islets and pancreatic ductal cells (Pdx1-hGLP1R:Glp1r-/- mice). Transgene expression restored GLP-1R-dependent stimulation of cAMP and Akt phosphorylation in isolated islets, conferred GLP-1R-dependent stimulation of β cell proliferation, and was sufficient for restoration of GLP-1-stimulated insulin secretion in perifused islets. Systemic GLP-1R activation with the GLP-1R agonist exendin-4 had no effect on food intake, hindbrain c-fos expression, or gastric emptying but improved glucose tolerance and stimulated insulin secretion in Pdx1-hGLP1R:Glp1r-/- mice. i.c.v. GLP-1R blockade with the antagonist exendin(9-39) impaired glucose tolerance in WT mice but had no effect in Pdx1-hGLP1R:Glp1r-/- mice. Nevertheless, transgenic expression of the pancreatic GLP-1R was sufficient to normalize both oral and i.p. glucose tolerance in Glp1r-/- mice. These findings illustrate that low levels of endogenous GLP-1 secreted from gut endocrine cells are capable of augmenting glucoregulatory activity via pancreatic GLP-1Rs independent of communication with neural pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Glucagon-Like Peptide 1 / physiology
  • Glucagon-Like Peptide-1 Receptor
  • Glucose / metabolism*
  • Glucose Tolerance Test
  • Homeostasis
  • Humans
  • Incretins / metabolism*
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Neurosecretory Systems / physiology
  • Pancreas / physiology*
  • Peptide Fragments / pharmacology
  • Receptors, Glucagon / antagonists & inhibitors
  • Receptors, Glucagon / deficiency
  • Receptors, Glucagon / genetics
  • Receptors, Glucagon / metabolism*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Signal Transduction


  • GLP1R protein, human
  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Incretins
  • Insulin
  • Peptide Fragments
  • Receptors, Glucagon
  • Recombinant Proteins
  • exendin (9-39)
  • Glucagon-Like Peptide 1
  • Glucose