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Activation of Phosphatidylinositol 3-Kinase Contributes to Insulin-Like Growth Factor I-Mediated Inhibition of Pancreatic ß-Cell Death

Department of Medicine, Veterans Affairs Chicago Healthcare System, Lakeside Division, and Northwestern University Medical School, Chicago, Illinois 60611

Address all correspondence and requests for reprints to: William L. Lowe, Jr., M.D., Center for Endocrinology, Metabolism, and Molecular Medicine, Tarry 15-703, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, Illinois 60611. E-mail: wlowe{at}nwu.edu.

To begin to determine whether IGF-I treatment represents a potential means of enhancing the survival of islet cell grafts after transplantation, the present studies established a model of ß-cell death secondary to loss of trophic support and examined the ability of IGF-I to prevent cell death. The studies were performed using the rat pancreatic ß-cell line, INS-1. Incubating INS-1 cells in RPMI 1640 and 0.25% BSA for 48 h increased cell death, as determined by lactate dehydrogenase release, compared with that of cells maintained in RPMI and 10% fetal calf serum. Addition of 100 ng/ml IGF-I to the serum-free medium decreased lactate dehydrogenase release to a level comparable to that found in cells maintained in fetal calf serum. Similar results were seen using a mouse ß-cell line, MIN6, infected with an adenovirus expressing IGF-I. Examination of IGF-I-stimulated signaling demonstrated that IGF-I increased the phosphorylation of protein kinase B in both cell lines, whereas IGF-I-induced phosphorylation of the MAPKs, ERK1 and -2, was observed only in INS-1 cells. The effect of IGF-I on phosphorylation of substrates of phosphatidylinositol 3-kinase (PI 3-kinase) or protein kinase B was also examined in INS-1 cells. IGF-I increased the phosphorylation of glycogen synthase kinase 3ß, BAD, FKHR, and p70^S6 kinase. Another pathway that has been shown to mediate the protective of IGF-I in some cell types is activation of cAMP response element-binding protein (CREB). IGF-I increased CREB phosphorylation at a concentration as low as 10 ng/ml, and this effect was inhibited by H89, a PKA inhibitor, and PD98059, a MAPK kinase inhibitor. Consistent with the effect of IGF-I on CREB phosphorylation, IGF-I increased the transcriptional activity of CREB, although it had no effect on CREB binding to DNA. Use of inhibitors of the PI 3-kinase (LY 294002) or ERK (PD98059) pathways or CREB phosphorylation (H89) in the cell death assay demonstrated partial abrogation of the protective effect of IGF-I with LY 294002. These data demonstrate that IGF-I protects pancreatic ß-cells from cell death secondary to loss of trophic support and that, although IGF-I activates several signaling pathways that contribute to its protective effect in other cell types, only activation of PI 3-kinase contributes to this effect in ß-cells.

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