GPRC6A mediates the effects of L-arginine on insulin secretion in mouse pancreatic islets

Endocrinology. 2012 Oct;153(10):4608-15. doi: 10.1210/en.2012-1301. Epub 2012 Aug 7.


L-arginine (l-Arg) is an insulin secretagogue, but the molecular mechanism whereby it stimulates insulin secretion from β-cells is not known. The possibility that l-Arg regulates insulin secretion through a G protein-coupled receptor (GPCR)-mediated mechanism is suggested by the high expression of the nutrient receptor GPCR family C group 6 member A (GPRC6A) in the pancreas and TC-6 β-cells and the finding that Gprc6a(-/]minus]) mice have abnormalities in glucose homeostasis. To test the direct role of GPRC6A in regulating insulin secretion, we evaluated the response of pancreatic islets derived from Gprc6a(-/]minus]) mice to L-Arg. We found that the islet size and insulin content were decreased in pancreatic islets from Gprac6a(-/]minus]) mice. These alterations were selective for β-cells, because there were no abnormalities in serum glucagon levels or glucagon content of islets derived from Gprac6a(-/]minus]) mice. Significant reduction was observed in both the pancreatic ERK response to L-Arg administration to Gprc6a(-/]minus]) mice in vivo and L-Arg-induced insulin secretion and production ex vivo in islets isolated from Gprc6a(-/]minus]) mice. L-Arg stimulation of cAMP accumulation in isolated islets isolated from Gprc6a(-/]minus]) mice was also diminished. These findings suggest that l-Arg stimulation of insulin secretion in β-cells is mediated, at least in part, through GPRC6A activation of cAMP pathways.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Arginine / pharmacology*
  • Cyclic AMP / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Glucagon / metabolism
  • Glucose / metabolism
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism*
  • Mice
  • Mice, Knockout
  • Phosphorylation
  • Receptors, G-Protein-Coupled / metabolism*


  • GPRC6A protein, mouse
  • Insulin
  • Receptors, G-Protein-Coupled
  • Glucagon
  • Arginine
  • Cyclic AMP
  • Extracellular Signal-Regulated MAP Kinases
  • Glucose