title: Chronic GLP-1 receptor activation by exendin-4 induces expansion of pancreatic duct glands in rats and accelerates formation of dysplastic lesions and chronic pancreatitis in the Kras(G12D) mouse model.
abstract: Pancreatic duct glands (PDGs) have been hypothesized to give rise to pancreatic intraepithelial neoplasia (PanIN). Treatment with the glucagon-like peptide (GLP)-1 analog, exendin-4, for 12 weeks induced the expansion of PDGs with mucinous metaplasia and columnar cell atypia resembling low-grade PanIN in rats. In the pancreata of Pdx1-Cre; LSL-Kras(G12D) mice, exendin-4 led to acceleration of the disruption of exocrine architecture and chronic pancreatitis with mucinous metaplasia and increased formation of murine PanIN lesions. PDGs and PanIN lesions in rodent and human pancreata express the GLP-1 receptor. Exendin-4 induced proproliferative signaling pathways in human pancreatic duct cells, cAMP-protein kinase A and mitogen-activated protein kinase phosphorylation of cAMP-responsive element-binding protein, and increased cyclin D1 expression. These GLP-1 effects were more pronounced in the presence of an activating mutation of Kras and were inhibited by metformin. These data reveal that GLP-1 mimetic therapy may induce focal proliferation in the exocrine pancreas and, in the context of exocrine dysplasia, may accelerate formation of neoplastic PanIN lesions and exacerbate chronic pancreatitis.
authors.affiliation: Larry L. Hillblom Islet Research Center, University of California Los Angeles (UCLA), David Geffen School of Medicine, Los Angeles, California, USA. bgier@mednet.ucla.edu
authors.forename: Belinda
authors.initials: B
authors.lastname: Gier
authors.forename: Aleksey V
authors.initials: AV
authors.lastname: Matveyenko
authors.forename: David
authors.initials: D
authors.lastname: Kirakossian
authors.forename: David
authors.initials: D
authors.lastname: Dawson
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Dry
authors.forename: Peter C
authors.initials: PC
authors.lastname: Butler
mesh_terms: D000818:Animals; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D009154:Mutation; D010183:Pancreatic Ducts / Q000187:drug effects* / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced* / Q000473:pathology; D010455:Peptides / Q000494:pharmacology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000819:agonists* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology*
chemical_list: C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D018398:Homeodomain Proteins; D007004:Hypoglycemic Agents; D010455:Peptides; D018027:Receptors, Glucagon; D015534:Trans-Activators; D014688:Venoms; C084010:pancreatic and duodenal homeobox 1 protein; D008687:Metformin; D000077270:Exenatide; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)