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Activation of phosphatidylinositol 3-kinase contributes to insulin-like growth factor-1 mediated inhibition of pancreatic beta cell death.

Authors
 Wenli Liu  ;  Catherine Chin Chance  ;  Eun Jig Lee  ;  William L. Lowe Jr 
Citation
 ENDOCRINOLOGY, Vol.143(10) : 3802-3812, 2002 
Journal Title
 ENDOCRINOLOGY 
ISSN
 0013-7227 
Issue Date
2002
MeSH
Animals ; Cell Death/drug effects ; Cell Death/physiology ; Cell Line ; Chromones/pharmacology ; Culture Media, Serum-Free ; Cyclic AMP Response Element-Binding Protein/drug effects ; Cyclic AMP Response Element-Binding Protein/physiology ; Enzyme Activation/physiology ; Enzyme Inhibitors/pharmacology ; Flavonoids/pharmacology ; Insulin-Like Growth Factor I/pharmacology ; Insulin-Like Growth Factor I/physiology* ; Islets of Langerhans/drug effects ; Islets of Langerhans/physiology* ; Mitogen-Activated Protein Kinases/metabolism ; Morpholines/pharmacology ; Phosphatidylinositol 3-Kinases/metabolism* ; Phosphorylation/drug effects ; Protein-Serine-Threonine Kinases* ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-akt ; Rats
Abstract
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 β-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 β-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 β-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 3β, BAD, FKHR, and p70S6 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 β-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 β-cells.
Full Text
http://press.endocrine.org/doi/abs/10.1210/en.2002-220058
DOI
10.1210/en.2002-220058
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Lee, Eun Jig(이은직) ORCID logo https://orcid.org/0000-0002-9876-8370
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/144461
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