Exendin-4 prevented pancreatic beta cells from apoptosis in (Type I) diabetic mouse via keap1-Nrf2 signaling

Abstract

Type I diabetes mellitus (TIDM) serves as a large contributor to morbidity as well as mortality globally with persistently elevating prevalence. It is known that oxidative damage by free radicals participates in etiology, complications, as well as progression of TIDM. In our research, we demonstrate that Keap1-Nrf2-ARE pathway was stimulated by exendin-4 treatment during the development of type I diabetes in murine TIDM model as well as in pancreatic β-cells. We also observed excessive reactive oxygen species (ROS) production, low level of cell death, and PKC phosphorylation on exendine-4 treatment. Nrf2 knockdown led to suppression of ROS generation as well as increasing apoptosis. Moreover, siRNA-mediated Nrf2 down-regulation attenuated the suppressive effect of exendin-4 in pancreatic β-cell viability, through modulating apoptosis promoting- and counteracting-proteins, Bax, and Bcl-2. Thus, the present study indicates exendin-4 mediates activation of Keap1-Nrf2-ARE pathway and may serve as a promising agent to treat TIDM. Impact statement: Nrf2 is an essential part of the defense mechanism of vertebrates and protects them from surrounding stress via participation in stimulated expression of detoxification as well as antioxidant enzymes. It also exerts a role in defending hosts from different stress in the environment, including reactive oxygen species. Our study investigates the role of exendin-4 on Nrf2 pathway as well as cell death in pancreatic β-cell and in non-obese diabetic mice. Result of study indicates exendin-4 mediates activation of Keap1-Nrf2-ARE pathway and may serve as a potential agent to treat type I diabetes mellitus. In our research, we observed excessive reactive oxygen species production, low level of cell death, and PKC phosphorylation on exendine-4 treatment. Nrf2 knockdown led to suppression of reactive oxygen species generation as well as increasing apoptosis. Moreover, siRNA-mediated Nrf2 down-regulation attenuated the suppressive effect of exendin-4 in pancreatic β-cell viability, via modulating apoptosis promoting- and counteracting-proteins, Bax, and Bcl-2.