title: Exendin-4 protects hypoxic islets from oxidative stress and improves islet transplantation outcome.
abstract: Oxidative stress produced during pancreatic islet isolation leads to significant β-cell damage. Homeostatic cytokines secreted subsequently to islet transplantation damage β-cells by generating oxygen free radicals. In this study, exendin-4, a glucagon-like peptide-1 analog improved islet transplantation outcome by increasing the survival of diabetic recipient mice from 58% to 100%. We hypothesized that this beneficial effect was due to the ability of exendin-4 to reduce oxidative stress. Further experiments showed that it significantly reduced the apoptotic rate of cultured β-cells subjected to hypoxia or to IL-1β. Reduction of apoptotic events was confirmed in pancreatic islet grafts of exendin-4-treated mice. Exendin-4 enhanced Akt phosphorylation of β-cells and insulin released from them. It even augmented insulin secretion from islets cultivated at hypoxic conditions. Exposure to hypoxia led to a decrease in the activation of Akt, which was reversed when β-cells were pretreated with exendin-4. Moreover, exendin-4 increased the activity of redox enzymes in a hypoxia-treated β-cell line and reduced reactive oxygen species production in isolated pancreatic islets. Recovery from diabetes in mice transplanted with hypoxic islets was more efficient when they received exendin-4. In conclusion, exendin-4 rescued islets from oxidative stress caused by hypoxia or due to cytokine exposure. It improved the outcome of syngenic and xenogenic islet transplantation.
authors.affiliation: Medical Clinic and Policlinic 3, Justus Liebig University, D-35392 Giessen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Padmasekar
authors.forename: N
authors.initials: N
authors.lastname: Lingwal
authors.forename: B
authors.initials: B
authors.lastname: Samikannu
authors.forename: C
authors.initials: C
authors.lastname: Chen
authors.forename: H
authors.initials: H
authors.lastname: Sauer
authors.forename: T
authors.initials: T
authors.lastname: Linn
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000601:surgery*; D004195:Disease Models, Animal; D000077270:Exenatide; D006085:Graft Survival / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000637:transplantation; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects*; D016381:Islets of Langerhans Transplantation / Q000379:methods* / Q000401:mortality; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects*; D010455:Peptides / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000032:analysis; D013552:Swine; D014688:Venoms / Q000494:pharmacology*
chemical_list: D007004:Hypoglycemic Agents; D010455:Peptides; D017382:Reactive Oxygen Species; D014688:Venoms; D000077270:Exenatide