title: Exendin-4 protects pancreatic beta cells from the cytotoxic effect of rapamycin by inhibiting JNK and p38 phosphorylation.
abstract: It has been reported that the immunosuppressant rapamycin decreases the viability of pancreatic beta cells. In contrast, exendin-4, an analogue of glucagon-like peptide-1, has been found to inhibit beta cell death and to increase beta cell mass. We investigated the effects of exendin-4 on the cytotoxic effect of rapamycin in beta cells. Incubation with 10 nM rapamycin induced cell death in 12 h in murine beta cell line MIN6 cells and Wistar rat islets, but not when coincubated with 10 nM exendin-4. Rapamycin was found to increase phosphorylation of c-Jun amino-terminal kinase (JNK) and p38 in 30 minutes in MIN6 cells and Wistar rat islets while exendin-4 decreased their phosphorylation. Akt and extracellular signal-regulated kinase (ERK) were not involved in the cytoprotective effect of exendin-4. These results indicate that exendin-4 may exert its protective effect against rapamycin-induced cell death in pancreatic beta cells by inhibiting JNK and p38 signaling.
authors.affiliation: Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kawasaki
authors.forename: S
authors.initials: S
authors.lastname: Harashima
authors.forename: M
authors.initials: M
authors.lastname: Sasaki
authors.forename: E
authors.initials: E
authors.lastname: Mukai
authors.forename: Y
authors.initials: Y
authors.lastname: Nakamura
authors.forename: N
authors.initials: N
authors.lastname: Harada
authors.forename: K
authors.initials: K
authors.lastname: Toyoda
authors.forename: A
authors.initials: A
authors.lastname: Hamasaki
authors.forename: S
authors.initials: S
authors.lastname: Yamane
authors.forename: C
authors.initials: C
authors.lastname: Yamada
authors.forename: Y
authors.initials: Y
authors.lastname: Yamada
authors.forename: Y
authors.initials: Y
authors.lastname: Seino
authors.forename: N
authors.initials: N
authors.lastname: Inagaki
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003470:Culture Media; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D000077270:Exenatide; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005434:Flow Cytometry; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000473:pathology; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors*; D010455:Peptides / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D020123:Sirolimus / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D014688:Venoms / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; D003470:Culture Media; D007328:Insulin; D010455:Peptides; D014688:Venoms; D000077270:Exenatide; D019869:Phosphatidylinositol 3-Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020123:Sirolimus