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This version published online on November 14, 2003
Endocrinology, doi:10.1210/en.2003-1274
A more recent version of this article appeared on February 1, 2004
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Submitted on September 23, 2003
Accepted on November 3, 2003

IGF-I/IGF-Binding Protein-3 (IGFBP-3) Complex: Therapeutic Efficacy and Mechanism of Protection Against Type 1 Diabetes

Wei Chen1, Konstantin V. Salojin1, Qing-Sheng Mi1, Marsha Grattan1, T. Craig Meagher1, Peter Zucker1, and Terry L. Delovitch1*

1 Autoimmunity/Diabetes Group, Robarts Research Institute, 1400 Western Road, London, Ontario N6G 2V4, Canada; and the Department of Microbiology and Immunology, University of Western Ontario; London, ON N6A 5C1, Canada

* To whom correspondence should be addressed. E-mail: del{at}robarts.ca.

IGF-I regulates islet {beta} 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/IGFBP-3 complex affords increased protection against T1D and whether this occurs by influencing T cell function and/or islet {beta} 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 upregulated CCL4 and downregulated CCL3 gene expression in pancreatic draining lymph nodes, activation of the phosphatidylinositol 3-kinase (PI3-K) and Akt/protein kinase B (Akt1) signaling pathway of {beta} cells, reduced {beta} cell apoptosis and stimulation of {beta} cell replication. Reduced {beta} cell apoptosis resulted from elevated Bcl-2 and Bcl-XL activity and diminished caspase-9 activity, indicating a novel role for a mitochondrial-dependent pathway of {beta} cell death. Thus, IGF-I/IGFBP-3 affords more efficient protection from insulitis, {beta} cell destruction and T1D than IGF-I, and this complex may represent an efficacious therapeutic treatment for the prevention of T1D.
Key words: IGF-I/IGFBP-3 complex • NOD mice • type 1 diabetes




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