Glucagon-like peptide-1 promotes DNA synthesis, activates phosphatidylinositol 3-kinase and increases transcription factor pancreatic and duodenal homeobox gene 1 (PDX-1) DNA binding activity in beta (INS-1)-cells

Diabetologia. 1999 Jul;42(7):856-64. doi: 10.1007/s001250051238.


Aims/hypothesis: Glucagon-like peptide-1 is a potent glucoincretin hormone and a potentially important drug in the treatment of Type II (non-insulin-dependent) diabetes mellitus. We have investigated whether it acts as a growth factor in beta (INS-1)-cells and have studied the signalling pathways and transcription factors implicated in this process.

Methods: Cell proliferation was assessed by tritiated thymidine incorporation measurements. We have examined the action of glucagon-like peptide-1 on the enzymatic activity of phosphatidylinositol 3-kinase. The DNA binding activity of transcription factors was investigated by electrophoretic mobility shift assay. Measurements of mRNA were done using the northern technique.

Results: Glucagon-like peptide-1 caused an increase in tritiated thymidine incorporation in beta (INS-1)-cells and phosphatidylinositol 3-kinase activity in a dose-dependent manner non-additively with glucose. The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 blocked the effects of glucagon-like peptide-1 on DNA synthesis. Transcription factor pancreatic and duodenal homebox gene 1 (PDX-1) DNA binding activity was increased by glucagon-like peptide-1 at 3 or 11 mmol/l glucose and the phosphatidylinositol 3-kinase inhibitor LY294002 suppressed the action of glucagon-like peptide-1 on PDX-1 DNA binding activity. Glucagon-like peptide-1 and glucose alone did not change activating protein-1 DNA binding activity. They synergised, however, to increase the activity of activating protein-1. Glucagon-like peptide-1 also increased the expression of PDX-1, glucose transporter 2, glucokinase and insulin mRNAs. Finally, glucagon-like peptide-1 increased the incorporation of tritiated thymidine in isolated rat islets.

Conclusion/interpretation: The results suggest that glucagon-like peptide-1 may act as a growth factor for the beta cell by a phosphatidylinositol 3-kinase mediated event. Glucagon-like peptide-1 could also regulate the expression of the insulin gene and genes encoding enzymes implicated in glucose transport and metabolism through the phosphatidylinositol 3-kinase/PDX-1 transduction signalling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstadienes
  • Animals
  • Chromones
  • DNA / biosynthesis
  • DNA / drug effects*
  • DNA-Binding Proteins / metabolism
  • Duodenum / metabolism
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors
  • Genes, Homeobox
  • Glucagon / genetics
  • Glucagon / pharmacology*
  • Glucagon-Like Peptide 1
  • Glucose / pharmacology
  • Humans
  • Insulin / genetics
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / growth & development
  • Islets of Langerhans / physiology
  • Morpholines
  • Nifedipine / pharmacology
  • Pancreas / metabolism
  • Peptide Fragments / genetics
  • Peptide Fragments / pharmacology*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Potassium Chloride / pharmacology
  • Protein Precursors / genetics
  • Protein Precursors / pharmacology*
  • RNA, Messenger / analysis
  • Rats
  • Rats, Wistar
  • Signal Transduction
  • Transcription Factor AP-1 / metabolism
  • Transcription Factors / genetics*
  • Tumor Cells, Cultured
  • Wortmannin


  • Androstadienes
  • Chromones
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Insulin
  • Morpholines
  • Peptide Fragments
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Precursors
  • RNA, Messenger
  • Transcription Factor AP-1
  • Transcription Factors
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Potassium Chloride
  • Glucagon-Like Peptide 1
  • DNA
  • Glucagon
  • Nifedipine
  • Glucose
  • Wortmannin