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Insulin-Like Growth Factor (IGF)-I/IGF-Binding Protein-3 Complex: Therapeutic Efficacy and Mechanism of Protection against Type 1 Diabetes

Autoimmunity/Diabetes Group (W.C., K.V.S., Q.-S.M., M.G., T.C.M., P.Z., T.L.D.), Robarts Research Institute, London, Ontario N6G 2V4, Canada; and the Department of Microbiology and Immunology (T.C.M., T.L.D.), University of Western Ontario, London, Ontario N6A 5C1, Canada

Address all correspondence and requests for reprints to: Dr. Terry L. Delovitch, Director, Autoimmunity/Diabetes Group, Robarts Research Institute, 1400 Western Road, London, Ontario N6G 2V4, Canada. E-mail: del{at}robarts.ca.

IGF-I regulates islet ß-cell growth, survival, and metabolism and protects against type 1 diabetes (T1D). However, the therapeutic efficacy of free IGF-I may be limited by its biological half-life in vivo. We investigated whether prolongation of its half-life as an IGF-I/IGF binding protein (IGFBP)-3 complex affords increased protection against T1D and whether this occurs by influencing T cell function and/or islet ß-cell growth and survival. Administration of IGF-I either alone or as an IGF-I/IGFBP-3 complex reduced the severity of insulitis and delayed the onset of T1D in nonobese diabetic mice, but IGF-I/IGFBP-3 was significantly more effective. Protection from T1D elicited by IGF-I/IGFBP-3 was mediated by up-regulated CCL4 and down-regulated CCL3 gene expression in pancreatic draining lymph nodes, activation of the phosphatidylinositol 3-kinase and Akt/protein kinase B signaling pathway of ß-cells, reduced ß-cell apoptosis, and stimulation of ß-cell replication. Reduced ß-cell apoptosis resulted from elevated Bcl-2 and Bcl-X_L activity and diminished caspase-9 activity, indicating a novel role for a mitochondrial-dependent pathway of ß-cell death. Thus, IGF-I/IGFBP-3 affords more efficient protection from insulitis, ß-cell destruction, and T1D than IGF-I, and this complex may represent an efficacious therapeutic treatment for the prevention of T1D.

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