title: Oleic acid and glucose regulate glucagon-like peptide 1 receptor expression in a rat pancreatic ductal cell line.
abstract: The glucagon-like peptide 1 receptor (GLP1R) plays a critical role in glucose metabolism and has become an important target for a growing class of drugs designed to treat type 2 diabetes. In vitro studies were designed to investigate the effect of the GLP1R agonist, exenatide (Ex4), in "on-target" RIN-5mF (islet) cells as well as in "off-target" AR42J (acinar) and DSL-6A/C1 (ductal) cells in a diabetic environment. Ex4 increased islet cell proliferation but did not affect acinar cells or ductal cells at relevant concentrations. A high caloric, high fat diet is a risk factor for impaired glucose tolerance and type-2 diabetes. An in vitro Oleic acid (OA) model was used to investigate the effect of Ex4 in a high calorie, high fat environment. At 0.1 and 0.4mM, OA mildly decreased the proliferation of all pancreatic cell types. Ex4 did not potentiate the inhibitory effect of OA on cell proliferation. Akt phosphorylation in response to Ex4 was diminished in OA-treated ductal cells. GLP1R protein detected by western blot was time and concentration dependently decreased after glucose stimulation in OA-treated ductal cells. In ductal cells, OA treatment altered the intracellular localization of GLP1R and its co-localization with early endosome and recycling endosomes. Chloroquine (lysosomal inhibitor), N-acetyl-l-cysteine (reactive oxygen species scavenger) and wortmannin (a phosphatidylinositol-3-kinase inhibitor), fully or partially, rescued GLP1R protein in OA-pretreated, glucose-stimulated ductal cells. The impact of altered regulation on phenotype/function is presently unknown. However, these data suggest that GLP1R regulation in ductal cells can be altered by a high fat, high calorie environment.
authors.affiliation: Division of Drug Safety Research, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Leshuai W
authors.initials: LW
authors.lastname: Zhang
authors.forename: Grainne A
authors.initials: GA
authors.lastname: McMahon Tobin
authors.forename: Rodney L
authors.initials: RL
authors.lastname: Rouse
mesh_terms: D061354:Acinar Cells / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D000077270:Exenatide; D005455:Fluorescent Antibody Technique; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D018613:Microscopy, Confocal; D019301:Oleic Acid / Q000494:pharmacology*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010183:Pancreatic Ducts / Q000187:drug effects* / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation; D051381:Rats; D018027:Receptors, Glucagon / Q000819:agonists / Q000096:biosynthesis*; D013268:Stimulation, Chemical; D014617:Vacuoles / Q000187:drug effects; D014688:Venoms / Q000494:pharmacology
chemical_list: C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D019301:Oleic Acid; D000077270:Exenatide; D051058:Oncogene Protein v-akt; D005947:Glucose