A selective small molecule glucagon-like peptide-1 secretagogue acting via depolarization-coupled Ca(2+) influx

J Endocrinol. 2009 Jun;201(3):361-7. doi: 10.1677/JOE-08-0528. Epub 2009 Mar 30.


Glucagon-like peptide-1 (GLP-1) is an incretin hormone that potentiates insulin secretion in a glucose-dependent manner. Selective GLP-1 secretagogue would be one of the potential therapeutic targets for type 2 diabetes. Here, we describe a newly identified small molecule compound (compound A) that stimulates secretion of GLP-1 in murine enteroendocrine cell lines, STC-1 and GLUTag cells, and in primary cultured fetal rat intestinal cells (FRIC). The underlying mechanism by which compound A stimulated GLP-1 secretion was also examined. Compound A stimulated GLP-1 secretion from STC-1 cells in a concentration-dependent manner, and also from GLUTag cells and FRIC. The action of compound A was selective against other tested endocrine functions such as secretion of insulin from rat islets, growth hormone from rat pituitary gland cells, and norepinephrine from rat PC-12 cells. In STC-1 cells, the compound A-stimulated GLP-1 secretion was neither due to cyclic AMP production nor to Ca(2+) release from intracellular stores, but to extracellular Ca(2+) influx. The response was inhibited by the presence of either L-type Ca(2+) channel blockers or K(+) ionophore. Perforated-patch clamp study revealed that compound A induces membrane depolarization. These results suggest that neither Galphas- nor Galphaq-coupled signaling account for the mechanism of action, but depolarization-coupled Ca(2+) influx from extracellular space is the primary cause for the GLP-1 secretion stimulated by compound A. Identifying a specific target molecule for compound A will reveal a selective regulatory pathway that leads to depolarization-mediated GLP-1 secretion.

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Calcium / physiology
  • Calcium Channel Agonists / pharmacology*
  • Calcium Channel Blockers / pharmacology
  • Cells, Cultured
  • Drug Evaluation, Preclinical
  • Enteroendocrine Cells / drug effects
  • Enteroendocrine Cells / metabolism
  • Female
  • Glucagon-Like Peptide 1 / metabolism*
  • Isoindoles / pharmacology
  • Male
  • Membrane Potentials / drug effects*
  • Membrane Potentials / physiology
  • Mice
  • Oxazoles / pharmacology
  • PC12 Cells
  • Pregnancy
  • Rats
  • Rats, Wistar
  • Secretory Pathway / drug effects*
  • Substrate Specificity
  • Verapamil / pharmacology


  • 3-(1-methylethyl)-9b-phenyl-(1,3)oxazolo(2,3-a)isoindole-2,5(3H,9bH)-dione
  • Calcium Channel Agonists
  • Calcium Channel Blockers
  • Isoindoles
  • Oxazoles
  • Glucagon-Like Peptide 1
  • Verapamil
  • Calcium