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Published online February 5, 2008
Diabetes 57:1205-1215, 2008
DOI: 10.2337/db07-1214
© 2008 by the American Diabetes Association
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Exendin-4 Protects β-Cells From Interleukin-1β–Induced Apoptosis by Interfering With the c-Jun NH2-Terminal Kinase Pathway

Mourad Ferdaoussi1,2, Saida Abdelli1,2, Jiang-Yan Yang2,3, Marion Cornu3,4, Guy Niederhauser1,2, Dimitri Favre1,2, Christian Widmann2,3, Romano Regazzi2, Bernard Thorens3,4, Gérard Waeber1, and Amar Abderrahmani1,2

1 Service of Internal Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
2 Department of Cellular Biology and Morphology, University of Lausanne, Lausanne, Switzerland
3 Department of Physiology, University of Lausanne, Lausanne, Switzerland
4 Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland

Corresponding author: Dr. Amar Abderrahmani, Privat-Docent, Department of Cellular Biology and Morphology, Rue du Bugnon 9, 1005 Lausanne, Switzerland. E-mail: amar.abderrahmani{at}unil.ch

OBJECTIVE— The pro-inflammatory cytokine interleukin-1β (IL-1β) generates pancreatic β-cells apoptosis mainly through activation of the c-Jun NH2-terminal kinase (JNK) pathway. This study was designed to investigate whether the long-acting agonist of the hormone glucagon-like peptide 1 (GLP-1) receptor exendin-4 (ex-4), which mediates protective effects against cytokine-induced β-cell apoptosis, could interfere with the JNK pathway.

RESEARCH DESIGN AND METHODS— Isolated human, rat, and mouse islets and the rat insulin-secreting INS-1E cells were incubated with ex-4 in the presence or absence of IL-1β. JNK activity was assessed by solid-phase JNK kinase assay and quantification of c-Jun expression. Cell apoptosis was determined by scoring cells displaying pycnotic nuclei.

RESULTS— Ex-4 inhibited induction of the JNK pathway elicited by IL-1β. This effect was mimicked with the use of cAMP-raising agents isobutylmethylxanthine and forskolin and required activation of the protein kinase A. Inhibition of the JNK pathway by ex-4 or IBMX and forskolin was concomitant with a rise in the levels of islet-brain 1 (IB1), a potent blocker of the stress-induced JNK pathway. In fact, ex-4 as well as IBMX and forskolin induced expression of IB1 at the promoter level through cAMP response element binding transcription factor 1. Suppression of IB1 levels with the use of RNA interference strategy impaired the protective effects of ex-4 against apoptosis induced by IL-1β.

CONCLUSIONS— The data establish the requirement of IB1 in the protective action of ex-4 against apoptosis elicited by IL-1β and highlight the GLP-1 mimetics as new potent inhibitors of the JNK signaling induced by cytokines.


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Copyright © 2008 by the American Diabetes Association.