Liraglutide Protects Pancreatic Islet From Ischemic Injury by Reducing Oxidative Stress and Activating Akt Signaling During Cold Preservation to Improve Islet Transplantation Outcomes

Abstract

Background. Islet transplantation is a promising therapy for patients with type 1 diabetes. However, ischemic injury to the donor islets during cold preservation leads to reduced islet quality and compromises transplant outcome. Several studies imply that liraglutide, a glucagon-like peptide-1 receptor agonist, has a positive effect on promoting islet survival, but its impact on islet cold-ischemic injury remains unexplored. Therefore, the aim of this study was to investigate whether liraglutide can improve islet transplantation efficacy by inhibiting cold-ischemic injury and to explore the underlying mechanisms. Methods. Liraglutide was applied in a mouse pancreas preservation model and a human islets cold-preservation model, and islet viability, function, oxidative stress levels were evaluated. Furthermore, islet transplantation was performed in a syngeneic mouse model and a human-to-nude mouse islet xenotransplantation model. Results. The supplementation of liraglutide in preservation solution improved islet viability, function, and reduced cell apoptosis. Liraglutide inhibited the oxidative stress of cold-preserved pancreas or islets through upregulating the antioxidant enzyme glutathione levels, inhibiting reactive oxygen species accumulation, and maintaining the mitochondrial membrane integrity, which is associated with the activation of Akt signaling. Furthermore, the addition of liraglutide during cold preservation of donor pancreas or donor islets significantly improved the subsequent transplant outcomes in both syngeneic mouse islet transplantation model and human-to-nude mouse islet xenotransplantation model. Conclusions. Liraglutide protects islets from cold ischemia-related oxidative stress during preservation and hence improved islet transplantation outcomes, and this protective effect of liraglutide in islets is associated with the activation of Akt signaling.