Low, but physiological, concentration of GLP-1 stimulates insulin secretion independent of the cAMP-dependent protein kinase pathway

J Pharmacol Sci. 2008 Nov;108(3):274-9. doi: 10.1254/jphs.08090fp. Epub 2008 Nov 6.


Glucagon-like peptide-1 (GLP-1) induces pancreatic insulin secretion via the cAMP-dependent protein kinase (PKA) pathway. However, the GLP-1 concentration used in the previous in vitro experiments was far from the in vivo concentrations. Alteration of plasma GLP-1 concentration at pM order lowers blood glucose concentration. In this study, we examined the GLP-1 action mechanism at a physiological concentration on insulin secretion. A high concentration of GLP-1 (10 nM) stimulated intracellular cAMP accumulation and insulin secretion was significantly inhibited by KT5720, a selective inhibitor of PKA. Low GLP-1 concentrations (1 pM) also increased insulin secretion without significant accumulation of intracellular cAMP, and KT5720 did not affect insulin secretion. Insulin secretion stimulated by 1 pM GLP-1 was reduced by inhibitors of calcium action, including verapamil, dantrolene, and BAPTA. Thus, we concluded that relatively low GLP-1 concentrations-comparable to in vivo blood concentrations-promoted insulin secretion independent of the cAMP-PKA pathway. This effect was dependent on intracellular Ca2+ concentration. The results of the present study may further the understanding of the dose-dependent response of GLP-1 signal transducing pathways and the complicated mechanism of insulin secretion. Studies of GLP-1 at physiologic concentrations may lead to new developments in studies of pancreatic beta-cell function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium Channel Blockers / pharmacology
  • Cell Line
  • Chelating Agents / pharmacology
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Glucagon-Like Peptide 1 / metabolism*
  • Humans
  • Insulin / metabolism*
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / enzymology
  • Insulin-Secreting Cells / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • Signal Transduction* / drug effects
  • Time Factors
  • Up-Regulation


  • Calcium Channel Blockers
  • Chelating Agents
  • Insulin
  • Protein Kinase Inhibitors
  • Glucagon-Like Peptide 1
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Calcium