Inhibition of eIF5A hypusination improves pancreatic islet transplantation outcomes by promoting ischemia tolerance

Pancreatic islet transplantation provides substantial benefits for individuals with Type 1 Diabetes (T1D). However, the low yield of the procedure limits its therapeutic potential, as multiple injections from different donors are needed to provide sufficient islets for a single recipient. Many islets are lost during preparation and transplantation, primarily due to ischemia/reperfusion injuries. GC7 (N1-guanyl-1,7-diaminoheptane), an inhibitor of eIF5A hypusination, improves the resistance of various cells to ischemia/reperfusion. Our study therefore explored whether ex-situ conditioning of pancreatic islets with GC7 during the preparation process could serve as a strategy to enhance the outcomes of pancreatic islet transplantation. Conditioning of mouse primary islets with GC7 at the digestion step of the pancreas significantly improved the procedure yield. Indeed, islets showed better survival at 24h and 72h after isolation and major protection against ischemia/reperfusion injury. Finally, the transplantation of a suboptimal number of islets under the renal capsule of hyperglycemic mice demonstrated superior functionality and survival of islets conditioned with GC7 compared to control islets. Collectively, these findings demonstrate that conditioning pancreatic islets with GC7 enhances their resistance to ischemia-reperfusion injury and significantly improves the efficiency of pancreatic islet transplantation. Hence the use of GC7 appears as a promising strategy to win one of the major challenges currently faced in the field of Type 1 diabetes.