Endocrinology. 2003 Nov 14 [Epub ahead of print]. Related Articles, Links
IGF-I/IGF-Binding Protein-3 (IGFBP-3) Complex: Therapeutic Efficacy and Mechanism of Protection Against Type 1 Diabetes.
Chen W, Salojin KV, Mi QS, Grattan M, Meagher TC, Zucker P, Delovitch TL.
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.
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.
PMID: 14617576 [PubMed - as supplied by publisher] |
