title: Pancreatic GLP-1 receptor activation is sufficient for incretin control of glucose metabolism in mice.
abstract: 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.
authors.affiliation: Department of Medicine, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Lamont
authors.forename: Yazhou
authors.initials: Y
authors.lastname: Li
authors.forename: Edwin
authors.initials: E
authors.lastname: Kwan
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Brown
authors.forename: Herbert
authors.initials: H
authors.lastname: Gaisano
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
mesh_terms: D000818:Animals; D052216:Glucagon-Like Peptide 1 / Q000502:physiology; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006706:Homeostasis; D006801:Humans; D054795:Incretins / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009490:Neurosecretory Systems / Q000502:physiology; D010179:Pancreas / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D054795:Incretins; D007328:Insulin; D010446:Peptide Fragments; D018027:Receptors, Glucagon; D011994:Recombinant Proteins; C083773:exendin (9-39); D052216:Glucagon-Like Peptide 1; D005947:Glucose