Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/80450
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Type: Journal article
Title: Insulin-like growth factor-II (IGF-II) prevents proinflammatory cytokine-induced apoptosis and significantly improves islet survival after transplantation
Author: Hughes, A.
Mohanasundaram, D.
Kireta, S.
Jessup, C.
Drogemuller, C.
Coates, P.
Citation: Transplantation, 2013; 95(5):671-678
Publisher: Lippincott Williams & Wilkins
Issue Date: 2013
ISSN: 0041-1337
1534-6080
Statement of
Responsibility: 
Hughes, Amy; Mohanasundaram, Daisy; Kireta, Svjetlana; Jessup, Claire F.; Drogemuller, Chris J.; Coates, P. Toby H.
Abstract: BACKGROUND: The early loss of functional islet mass (50-70%) due to apoptosis after clinical transplantation contributes to islet allograft failure. Insulin-like growth factor (IGF)-II is an antiapoptotic protein that is highly expressed in β-cells during development but rapidly decreases in postnatal life. METHODS: We used an adenoviral (Ad) vector to overexpress IGF-II in isolated rat islets and investigated its antiapoptotic action against exogenous cytokines interleukin-1β- and interferon-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 nonobese diabetic/severe combined immunodeficient 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%) versus Ad-GFP and untransduced control islets (63.2% ± 2.5% and 53.6% ± 2.3%, respectively). Ad-IGF-II overexpression during cytokine treatment resulted in a marked reduction in terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive apoptotic cells (8.3% ± 1.4%) versus 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 phosphatidylinositol 3-kinase/Akt signaling pathway. Transplantation of IGF-II overexpressing islets under the kidney capsule of diabetic mice restored euglycemia in 77.8% of recipients compared with 18.2% and 47.5% of Ad-GFP and untransduced control islet recipients, respectively (P<0.05, log-rank [Mantel-Cox] test). CONCLUSIONS: Antiapoptotic IGF-II decreases apoptosis in vitro and significantly improved islet transplant outcomes in vivo. Antiapoptotic gene transfer is a potentially powerful tool to improve islet survival after transplantation.
Keywords: Apoptosis; [beta]-Cells; Insulin-like growth factor-II; Gene therapy; Islet transplantation.
Rights: © 2013 by Lippincott Williams & Wilkins
RMID: 0020126474
DOI: 10.1097/TP.0b013e31827fa453
Appears in Collections:Medicine publications

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