Original Paper

IGF-1 Protects Against Dexamethasone-Induced Cell Death in Insulin Secreting INS-1 Cells Independent of AKT/PKB Phosphorylation
Diana Avram^{1, *}, Felicia Ranta^1,*, Anita M. Hennige², Susanne Berchtold^1, , Sabine Hopp², Hans-Ulrich Häring², Florian Lang¹, Susanne Ullrich<sup>1,2

1</sup>Institute of Physiology, University of Tübingen,
²Department of Internal Medicine IV, University Hospital Tübingen,
^*D.A. and F.R. contributed equally to the study and thus share first authorship,
Present address: Institute for Medical Microbiology, University Hospital Tübingen

Address of Corresponding Author

Cell Physiol Biochem 2008;21:455-462 (DOI: 10.1159/000129638)

  Key Words

• Apoptosis
• Proliferation
• Insulin secreting cells
• Dexamethasone
• IRS-2
• PI3K
• PKB/Akt
• ERK
• Phosphorylation

  Abstract

Appropriate insulin secretion depends on -cell mass that is determined by the balance between cell proliferation and death. IGF-1 stimulates proliferation and protects against apoptosis. In contrast, glucocorticoids promote cell death. In this study we examined molecular interactions of the glucocorticoid dexamethasone (dexa) with IGF-1 signalling pathways in insulin secreting INS-1 cells. IGF-1 (50 ng/ml) increased the growth rate and stimulated BrdU incorporation, while dexa (100 nmol/l) inhibited cell growth, BrdU incorporation and induced apoptosis. Dexa-induced cell death was partially antagonized by IGF-1. This protection was further increased by LY294002 (10 µmol/l), an inhibitor of PI3 kinase. In contrast, MAP kinase inhibitor PD98059 (10 µmol/l) significantly reduced the protective effect of IGF-1. The analysis of signalling pathways by Western blotting revealed that dexa increased IRS-2 protein abundance while the expression of PI3K, PKB and ERK remained unchanged. Despite increased IRS-2 protein,IRS-2 tyrosine phosphorylation stimulated by IGF-1 was inhibited by dexa. Dexa treatment reduced basal PKB phosphorylation. However, IGF-1-mediated stimulation of PKB phosphorylation was not affected by dexa, but ERK phosphorylation was reduced. LY294002 restored IGF-1-induced ERK phosphorylation. These data suggest that dexa induces apoptosis in INS-1 cells by inhibiting phosphorylation of IRS-2, PKB and ERK. IGF-1 counteracts dexa-mediated apoptosis in the presence of reduced PKB but increased ERK phosphorylation.

Copyright © 2008 S. Karger AG, Basel

  Author Contacts

Prof. Dr. Susanne Ullrich
University of Tuebingen, Medizinische Klinik IV
Otfried-Müller-Strasse 10, 72076 Tübingen (Germany)
Tel. +49 7071 29 87 599, Fax: +49 7071 29 59 74
E-Mail susanne.ullrich@med.uni-tuebingen.de

  Article Information

Accepted: December 12, 2007
Published online: April 24, 2008
Number of Print Pages : 8