Introduction: The early loss of functional islet mass (50-70%) due to apoptosis following clinical transplantation contributes to islet allograft failure. Insulin-like Growth Factor-II (IGF-II) is an anti-apoptotic protein that is highly expressed in Β-cells during development, but rapidly decreases in post-natal life. Methods: We used an Adenoviral (Ad) vector to over express IGF-II in isolated rat islets and investigated its anti-apoptotic action against exogenous cytokines IL-1Β and IFN-Γ induced islet cell death in vitro. Using an immunocompromised marginal mass islet transplant model, the ability of Ad-IGF-II transduced rat islets to restore euglycemia in NOD-SCID diabetic recipients was assessed. Results: Ad-IGF-II transduction did not affect islet viability or function. Ad-IGF-II cytokine treated islets exhibited decreased cell death (40 ± 2.8%) vs. Ad-GFP and untransduced control islets (63.2 ± 2.5% and 53.6 ± 2.3%, respectively). Ad-IGF-II over expression during cytokine treatment resulted in a marked reduction in TUNEL positive apoptotic cells (8.3 ± 1.4%) vs. Ad-GFP control (41 ± 4.2%) and untransduced control islets (46.5 ± 6.2%). Western blot analysis confirmed that IGF-II inhibits apoptosis via activation of the PI3K/Akt signalling pathway. Transplantation of IGF-II over expressing islets under the kidney capsule of diabetic mice restored euglycemia in 78% of recipients, compared to 18% and 47% of Ad-GFP and untransduced control islet recipients, respectively (p<0.05 Log-rank (Mantel Cox)). Ad-IGF-II recipient mice stabilized and slightly increased their weight following transplantation, while this was not the case for mice receiving untransduced or Ad-GFP transduced islet grafts, p<0.0001 (1way ANOVA). Conclusions: Anti-apoptotic IGF-II decreases apoptosis in vitro and significantly improved islet transplant outcomes in vivo. Anti-apoptotic gene transfer is a potentially powerful tool to improve islet survival post-transplantation.

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