Glucagon-like peptide-1 prevents beta cell glucolipotoxicity

Diabetologia. 2004 May;47(5):806-15. doi: 10.1007/s00125-004-1379-6. Epub 2004 Apr 17.


Aims/hypothesis: We have provided evidence that glucagon-like peptide-1, a potential therapeutic agent in the treatment of diabetes, activates phosphatidylinositol-3 kinase/protein kinase B signalling in the pancreatic beta cell. Since this pathway promotes cell survival in a variety of systems, we tested whether glucagon-like peptide-1 protects beta cells against cell death induced by elevated glucose and/or non-esterified fatty acids.

Methods: Human islets and INS832/13 cells were cultured at glucose concentrations of 5 or 25 mmol/l in the presence or absence of palmitate. Apoptosis was evaluated by monitoring DNA fragmentation and chromatin condensation. Wild-type and protein kinase B mutants were overexpressed in INS832/13 cells using adenoviruses. Nuclear factor-kappa B DNA binding was assayed by electrophoretic mobility shift assay.

Results: In human pancreatic beta cells and INS832/13 cells, glucagon-like peptide-1 prevented beta cell apoptosis induced by elevated concentrations of (i) glucose (glucotoxicity), (ii) palmitate (lipotoxicity) and (iii) both glucose and palmitate (glucolipotoxicity). Overexpression of a dominant-negative protein kinase B suppressed the anti-apoptotic action of glucagon-like peptide-1 in INS832/13 cells, whereas a constitutively active protein kinase B prevented beta cell apoptosis induced by elevated glucose and palmitate. Glucagon-like peptide-1 enhanced nuclear factor-kappa B DNA binding activity and stimulated the expression of inhibitor of apoptosis protein-2 and Bcl-2, two anti-apoptotic genes under the control of nuclear factor-kappa B. Inhibition of nuclear factor-kappa B by BAY 11-7082 abolished the prevention of glucolipotoxicity by glucagon-like peptide-1.

Conclusions/interpretation: The results demonstrate a potent protective effect of glucagon-like peptide-1 on beta cell gluco-, lipo- and glucolipotoxicity. This effect is mediated via protein kinase B activation and possibly its downstream target nuclear factor-kappa B.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Cell Line
  • Cells, Cultured
  • Glucagon
  • Glucagon-Like Peptide 1
  • Glucagon-Like Peptides
  • Glucose / toxicity*
  • Humans
  • Islets of Langerhans / cytology*
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / pathology
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • Nitriles / pharmacology
  • Palmitic Acid / toxicity*
  • Peptide Fragments / pharmacology*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Sulfones / pharmacology


  • 3-(4-methylphenylsulfonyl)-2-propenenitrile
  • NF-kappa B
  • Nitriles
  • Peptide Fragments
  • Proto-Oncogene Proteins
  • Sulfones
  • glucagon-like peptide 1 (7-36)amide
  • Palmitic Acid
  • Glucagon-Like Peptides
  • Glucagon-Like Peptide 1
  • Glucagon
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Glucose