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

• Published in: The Journal of clinical investigation Vol. 122; no. 1; pp. 388 - 402
• Main Authors: Lamont, Benjamin J, Li, Yazhou, Kwan, Edwin, Brown, Theodore J, Gaisano, Herbert, Drucker, Daniel J
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.01.2012
• Subjects: Animals; Biomedical research; Body fat; Food; Gene expression; Glucagon-Like Peptide 1 - physiology; Glucagon-Like Peptide-1 Receptor; Glucose; Glucose - metabolism; Glucose Tolerance Test; Homeostasis; Hormones; Humans; Incretins - metabolism; Insulin; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - physiology; Male; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Neurosecretory Systems - physiology; Nutrients; Pancreas; Pancreas - physiology; Pancreatic beta cells; Peptide Fragments - pharmacology; Peptides; Physiological aspects; Receptors, Glucagon - antagonists & inhibitors; Receptors, Glucagon - deficiency; Receptors, Glucagon - genetics; Receptors, Glucagon - metabolism; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Signal Transduction; Transgenic animals; Canada
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci42497

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.