HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ranta, F. Articles by Ullrich, S. Search for Related Content PubMed PubMed Citation Articles by Ranta, F. Articles by Ullrich, S. Social Bookmarking                What's this?

Dexamethasone Induces Cell Death in Insulin-Secreting Cells, an Effect Reversed by Exendin-4

¹ Institute of Physiology, University of Tübingen, Tübingen, Germany
² Department of Pharmacology, Institute of Pharmacy, University of Tübingen, Tübingen, Germany

Address correspondence and reprint requests to Dr. Susanne Ullrich, Institut für Physiologie, Gmelinstrasse 5, D-72076 Tübingen, Germany. E-mail: susanne.ullrich{at}uni-tuebingen.de

Abbreviations: BAD, proapoptotic protein of the Bcl-2 family; DAPI, 4'6-diamidino-2-phenylindole; GEF, guanine nucleotide exchange factor; GLP-1, glucagon-like peptide 1; PARP, poly-(ADP-) ribose polymerase; PKA, cAMP-dependent protein kinase; PNA, p-nitroanilide; TUNEL, transferase-mediated dUTP nick-end labeling

Glucocorticoid excess induces hyperglycemia, which may result in diabetes. The present experiments explored whether glucocorticoids trigger apoptosis in insulin-secreting cells. Treatment of mouse ß-cells or INS-1 cells with the glucocorticoid dexamethasone (0.1 µmol/l) over 4 days in cell culture increased the number of fractionated nuclei from 2 to 7 and 14%, respectively, an effect that was reversed by the glucocorticoid receptor antagonist RU486 (1 µmol/l). In INS-1 cells, dexamethasone increased the number of transferase-mediated dUTP nick-end labeling–staining positive cells, caspase-3 activity, and poly-(ADP-) ribose polymerase protein cleavage; decreased Bcl-2 transcript and protein abundance; dephosphorylated the proapoptotic protein of the Bcl-2 family (BAD) at serine155; and depolarized mitochondria. Dexamethasone increased PP-2B (calcineurin) activity, an effect abrogated by FK506. FK506 (0.1 µmol/l) and another calcineurin inhibitor, deltamethrin (1 µmol/l), attenuated dexamethasone-induced cell death. The stable glucagon-like peptide 1 analog, exendin-4 (10 nmol/l), inhibited dexamethasone-induced apoptosis in mouse ß-cells and INS-1 cells. The protective effect of exendin-4 was mimicked by forskolin (10 µmol/l) but not mimicked by guanine nucleotide exchange factor with the specific agonist 8CPT-Me-cAMP (50 µmol/l). Exendin-4 did not protect against cell death in the presence of cAMP-dependent protein kinase (PKA) inhibition by H89 (10 µmol/l) or KT5720 (5 µmol/l). In conclusion, glucocorticoid-induced apoptosis in insulin-secreting cells is accompanied by a downregulation of Bcl-2, activation of calcineurin with subsequent dephosphorylation of BAD, and mitochondrial depolarization. Exendin-4 protects against glucocorticoid-induced apoptosis, an effect mimicked by forskolin and reversed by PKA inhibitors.

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				Y. Fujinaka, K. Takane, H. Yamashita, and R. C. Vasavada Lactogens Promote Beta Cell Survival through JAK2/STAT5 Activation and Bcl-XL Upregulation J. Biol. Chem., October 19, 2007; 282(42): 30707 - 30717. [Abstract] [Full Text] [PDF]

				Y. Takano, K. Yamauchi, N. Hiramatsu, A. Kasai, K. Hayakawa, M. Yokouchi, J. Yao, and M. Kitamura Recovery and maintenance of nephrin expression in cultured podocytes and identification of HGF as a repressor of nephrin Am J Physiol Renal Physiol, May 1, 2007; 292(5): F1573 - F1582. [Abstract] [Full Text] [PDF]