Liver Ischemia Contributes to Early Islet Failure Following Intraportal Transplantation: Benefits of Liver Ischemic‐Preconditioning

Early graft failure following intraportal islet transplantation (IPIT) represents a major obstacle for successful islet transplantation. Here, we examined the role of islet emboli in the induction of early graft failure and utilized a strategy of ischemic‐preconditioning (IP) to prevent early islet destruction in a model of syngeneic IPIT in STZ‐induced diabetic mice. Numerous focal areas of liver necrosis associated with the islet emboli were observed within 24 h post‐IPIT. Pro‐inflammatory cytokines, IL‐1β and IL‐6, were significantly increased 3 h after IPIT, while TNF‐α was elevated for up to 5 days post‐IPIT. Caspase‐3 and terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labeling positive cells were observed in the transplanted islets trapped in areas of necrotic liver at 3 h and 1 day post‐IPIT. Hyperglycemia was corrected immediately following IPIT of 200 islets, but recurrence of hyperglycemia was observed within 14 days associated with a poor response to glucose challenge. IP, a procedure of pre‐exposure of the liver to transient ischemia and reperfusion, protected the liver from embolism‐induced ischemic injury and prevented early islet graft failure. These data suggest that islet embolism in the portal vein is a major cause of functional loss following IPIT that can be prevented by liver IP.

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