Insulin-like growth factor (IGF)-I/IGF-binding protein-3 complex: therapeutic efficacy and mechanism of protection against type 1 diabetes.
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/IGF binding protein (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 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 beta-cells, reduced beta-cell apoptosis, and stimulation of beta-cell replication. Reduced beta-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 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.
Chen
Wei
W
Autoimmunity/Diabetes Group, Robarts Research Institute, 1400 Western Road, London, Ontario N6G 2V4, Canada.
Salojin
Konstantin V
KV
Mi
Qing-Sheng
QS
Grattan
Marsha
M
Meagher
T Craig
TC
Zucker
Peter
P
Delovitch
Terry L
TL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002455:Cell Division; D018925:Chemokines / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology / Q000517:prevention & control*; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000517:prevention & control; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000008:administration & dosage* / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage* / Q000378:metabolism*; D007515:Islets of Langerhans / Q000201:enzymology / Q000473:pathology; D008198:Lymph Nodes / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010179:Pancreas; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes
D053453:Caspase 9; D020169:Caspases; D018925:Chemokines; D018972:Insulin-Like Growth Factor Binding Protein 3; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; C506434:Casp9 protein, mouse