Send to

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

Pancreatic GLP-1 receptor activation is sufficient for incretin control of glucose metabolism in mice.

Author information

Department of Medicine, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.


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.

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for American Society for Clinical Investigation Icon for PubMed Central
Loading ...
Support Center