title: Glucagon-like peptide-1 receptor agonists increase pancreatic mass by induction of protein synthesis.
abstract: Glucagon-like peptide-1 (GLP-1) controls glucose homeostasis by regulating secretion of insulin and glucagon through a single GLP-1 receptor (GLP-1R). GLP-1R agonists also increase pancreatic weight in some preclinical studies through poorly understood mechanisms. Here we demonstrate that the increase in pancreatic weight following activation of GLP-1R signaling in mice reflects an increase in acinar cell mass, without changes in ductal compartments or β-cell mass. GLP-1R agonists did not increase pancreatic DNA content or the number of Ki67(+) cells in the exocrine compartment; however, pancreatic protein content was increased in mice treated with exendin-4 or liraglutide. The increased pancreatic mass and protein content was independent of cholecystokinin receptors, associated with a rapid increase in S6 phosphorylation, and mediated through the GLP-1R. Rapamycin abrogated the GLP-1R-dependent increase in pancreatic mass but had no effect on the robust induction of Reg3α and Reg3β gene expression. Mass spectrometry analysis identified GLP-1R-dependent upregulation of Reg family members, as well as proteins important for translation and export, including Fam129a, eIF4a1, Wars, and Dmbt1. Hence, pharmacological GLP-1R activation induces protein synthesis, leading to increased pancreatic mass, independent of changes in DNA content or cell proliferation in mice.
authors.affiliation: Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Koehler
authors.affiliation: Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Laurie L
authors.initials: LL
authors.lastname: Baggio
authors.affiliation: Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Xiemin
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Tahmid
authors.initials: T
authors.lastname: Abdulla
authors.affiliation: Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Campbell
authors.affiliation: Gubra, Hørsholm, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Secher
authors.affiliation: Gubra, Hørsholm, Denmark.
authors.forename: Jacob
authors.initials: J
authors.lastname: Jelsing
authors.affiliation: Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Brett
authors.initials: B
authors.lastname: Larsen
authors.affiliation: Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada drucker@lunenfeld.ca.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D007150:Immunohistochemistry; D037181:Lectins, C-Type / Q000378:metabolism; D000069450:Liraglutide; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism*; D000073718:Pancreatitis-Associated Proteins; D010455:Peptides / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects; D011506:Proteins / Q000378:metabolism; D018027:Receptors, Glucagon / Q000819:agonists* / Q000378:metabolism*; D014688:Venoms / Q000494:pharmacology
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D037181:Lectins, C-Type; D000073718:Pancreatitis-Associated Proteins; D010455:Peptides; D011506:Proteins; D018027:Receptors, Glucagon; C490253:Reg3b protein, mouse; D014688:Venoms; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide