The eIF5A hypusination inhibitor GC7 improves tolerance of pancreatic beta cells to ischemia/reperfusion

Abstract

Transplantation of pancreatic islets, containing insulin-secreting beta cells, provides substantial benefits for individuals with type 1 diabetes. However, the low yield of the procedure limits its therapeutic potential, as many islets are lost during preparation and transplantation, primarily due to ischemia/reperfusion injuries and oxidative stress. N1-guanyl-1,7-diaminoheptane (GC7), an inhibitor of eIF5A hypusination, improves the resistance of various cells and organs to ischemia/reperfusion. Our study therefore explored whether GC7 treatment of beta cell models in vitro could serve as a strategy to enhance their resistance to ischemia/ reperfusion injuries. We treated rat INS-1 or mouse MIN6 cells with GC7 and analyzed insulin secretion, energetic metabolism, mitochondrial function, and both cell survival and oxidative stress under anoxia/reoxygenation conditions. In beta cells, eIF5A inhibition by GC7 treatment repressed transiently the mitochondrial activity, ATP production, and insulin secretion in response to glucose, which was linked to a metabolic shift from oxidative phosphorylation to anaerobic glycolysis. Following anoxia/reoxygenation to mimic ischemia/reperfusion, GC7 treatment significantly reduced oxidative stress while significantly improving cell survival by >50%. Collectively, these findings are a proof of concept, demonstrating that GC7 treatment of beta cells enhances their resistance to ischemia-reperfusion injury. Hence, the use of GC7 appears as a promising strategy to improve pancreatic islet survival during transplantation. NEW & NOTEWORTHY Treatment of rodent beta cell line with GC7, an inhibitor of eIF5A hypusination, reversibly slows down mitochondrial activity and shifts the cells’ energy metabolism toward anaerobic glycolysis. As a result, GC7 treatment transiently inhibits ATP production and insulin secretion in response to glucose. These changes enhance the resistance of pancreatic beta cell line to ischemia/reperfusion by reducing oxidative stress and improving cell survival, highlighting the potential anti-ischemic benefits of GC7 for pancreatic islet transplantation.