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Exendin-4 protects beta-cells from interleukin-1 beta-induced apoptosis by interfering with the c-Jun NH2-terminal

Mourad Ferdaoussi1, Saida Abdelli, Jiang-Yan Yang

  • 1Service of Internal Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.

Diabetes
|February 7, 2008
PubMed
Abstract

Insights

Glucagon-like peptide 1 (GLP-1) receptor agonist exendin-4 protects pancreatic beta-cells from interleukin-1 beta-induced apoptosis by inhibiting the JNK pathway via islet-brain 1 (IB1) induction.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Cell Biology

Background:

  • Interleukin-1 beta (IL-1 beta) induces pancreatic beta-cell apoptosis through the c-Jun NH(2)-terminal kinase (JNK) pathway.
  • Glucagon-like peptide 1 (GLP-1) receptor agonists, like exendin-4 (ex-4), show protective effects against cytokine-induced beta-cell apoptosis.

Purpose of the Study:

  • To investigate if exendin-4 interferes with the JNK pathway in cytokine-induced beta-cell apoptosis.
  • To elucidate the molecular mechanisms underlying the protective effects of ex-4.

Main Methods:

  • Isolated human, rat, and mouse islets and INS-1E cells were treated with ex-4 and IL-1 beta.
  • JNK activity and c-Jun expression were measured.
  • Cell apoptosis was assessed by nuclear morphology.
  • Islet-brain 1 (IB1) levels and promoter activity were analyzed.
  • RNA interference was used to suppress IB1.

Main Results:

  • Exendin-4 inhibited IL-1 beta-induced JNK pathway activation.
  • This inhibition was mimicked by cAMP-raising agents and required protein kinase A activation.
  • Ex-4 and cAMP-raising agents increased IB1 levels by activating the cAMP response element binding transcription factor 1.
  • Suppression of IB1 impaired the protective effects of ex-4 against IL-1 beta-induced apoptosis.

Conclusions:

  • Islet-brain 1 (IB1) is essential for the protective action of exendin-4 against IL-1 beta-induced beta-cell apoptosis.
  • GLP-1 mimetics are potent inhibitors of cytokine-induced JNK signaling.

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