Free fatty acids increase cytosolic free calcium and stimulate insulin secretion from beta-cells through activation of GPR40

Mol Cell Endocrinol. 2007 Jan 15;263(1-2):173-80. doi: 10.1016/j.mce.2006.09.013. Epub 2006 Nov 13.


Free fatty acids (FFA) cause a rise in cytosolic free Ca2+ ([Ca2+]i) and stimulate insulin release from pancreatic beta-cells. The G-protein coupled receptor GPR40 can be activated by medium- and long-chain FFA. We investigated a potential role for GPR40 in the generation of the FFA-induced Ca2+ signal and insulin secretion. [Ca2+]i was measured in primary mouse beta-cells and in INS-1 cells, and insulin secretion was assessed from INS-1 cells. GPR40 expression was determined by RT-PCR and downregulation of GPR40 expression by siRNA transfection was carried out in INS-1 cells. A number of saturated, mono- and polyunsaturated medium- and long-chain FFA caused a rise in [Ca2+]i both in primary mouse beta-cells and in INS-1 cells. By contrast, the short-chain saturated caproic acid was ineffective at concentrations up to 300 microM. In INS-1 cells, the FFA-induced Ca2+ signal required mobilization of internal Ca2+ and Ca2+ influx through voltage-sensitive Ca2+ channels. RT-PCR analysis revealed that GPR40 is expressed in INS-1 cells. Downregulation of GPR40 by specific siRNA treatment lead to a significant inhibition of the FFA-induced [Ca2+]i response and insulin secretion, indicating that the FFA-stimulated Ca2+ signal and insulin secretion involve activation of GPR40 in pancreatic beta-cells.

MeSH terms

  • Animals
  • Biological Transport
  • Calcium / metabolism*
  • Calcium Signaling
  • Cell Communication
  • Cells, Cultured
  • Cytosol / metabolism*
  • Fatty Acids, Nonesterified / pharmacology*
  • Female
  • Glucose / metabolism
  • Hypoglycemic Agents / metabolism
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism
  • Insulinoma / metabolism
  • Insulinoma / pathology
  • Islets of Langerhans / cytology
  • Islets of Langerhans / metabolism
  • Mice
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • RNA, Small Interfering / pharmacology
  • Rats
  • Receptors, G-Protein-Coupled / antagonists & inhibitors
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*


  • Fatty Acids, Nonesterified
  • Ffar1 protein, mouse
  • G-protein-coupled receptor 40, rat
  • Hypoglycemic Agents
  • Insulin
  • RNA, Small Interfering
  • Receptors, G-Protein-Coupled
  • Glucose
  • Calcium