Glucagon-like peptide-1 Inhibits Apoptosis of Insulin-Secreting Cells via a Cyclic 5'-adenosine Monophosphate-Dependent Protein Kinase A- And a Phosphatidylinositol 3-kinase-dependent Pathway

Endocrinology. 2003 Apr;144(4):1444-55. doi: 10.1210/en.2002-220897.

Abstract

The activation of the glucagon-like peptide-1 (GLP-1) receptor has been shown to have an important role in the functional activity of islet beta-cells and in the expansion of the islet cell mass. Constant remodeling of islet cell mass is mediated in vivo by proliferative and apoptotic stimuli to ensure a dynamic response to a changing demand for insulin. The present study was undertaken to investigate the biological activity of GLP-1 when cells were challenged by a proapoptotic stimulus. We have shown that activation of the GLP-1 receptor inhibits H(2)O(2)-induced apoptosis in a cultured mouse insulinoma cell line, termed MIN6. GLP-1 reduced DNA fragmentation and improved cell survival. This was mediated by an increased expression of the antiapoptotic proteins Bcl-2 and Bcl-xL. GLP-1 also prevented the H(2)O(2)-dependent cleavage of poly-(ADP-ribose)-polymerase. Inhibition of the GLP-1-dependent increase of cAMP by Rp-cAMP blocked the antiapoptotic action of GLP-1, as determined by DNA fragmentation and poly-(ADP-ribose)-polymerase assays and by detection of Bcl-2 and Bcl-xL protein levels. Investigation of the role of the protein kinases, PI-3 kinase (PI3K) and MAPK, by use of the inhibitors PD098059 and LY294002 demonstrated that the activation of PI3K, but not MAPK, was required to prevent proapoptotic events in cells exposed to H(2)O(2). The present study provides evidence that GLP-1 has an antiapoptotic action mediated by a cAMP- and PI3K-dependent signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Cyclic AMP / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • DNA / metabolism
  • Glucagon / antagonists & inhibitors
  • Glucagon / pharmacology*
  • Glucagon-Like Peptide 1
  • Hydrogen Peroxide / pharmacology
  • Insulinoma
  • Islets of Langerhans / cytology
  • Islets of Langerhans / metabolism*
  • Mice
  • Oxidants / pharmacology
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / pharmacology*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Protein Precursors / antagonists & inhibitors
  • Protein Precursors / pharmacology*
  • Signal Transduction / drug effects
  • Tumor Cells, Cultured

Substances

  • Oxidants
  • Peptide Fragments
  • Protein Precursors
  • Glucagon-Like Peptide 1
  • DNA
  • Glucagon
  • Hydrogen Peroxide
  • Cyclic AMP
  • Poly(ADP-ribose) Polymerases
  • Phosphatidylinositol 3-Kinases
  • Cyclic AMP-Dependent Protein Kinases