M. Ferdaoussi, Valérie Bergeron, M. Kebede
Oct 1, 2012
Citations
2
Influential Citations
9
Citations
Journal
Canadian Journal of Diabetes
Abstract
Abstract Free fatty acid receptor 1/G-protein-coupled receptor 40 (FFA1/GPR40) is activated by medium- to long-chain fatty acids (FA) and preferentially expressed in pancreatic β-cells. GPR40 mediates the acute potentiating effect of FA on glucose-stimulated insulin secretion, but not their chronic deleterious effects. As such, GPR40 is being considered as a new therapeutic target to enhance insulin secretion in type 2 diabetes mellitus. A number of preclinical studies and recent phase 2 clinical trials support the beneficial effects of a GPR40 agonist in type 2 diabetes. Recent studies from our laboratory identified protein kinase D as a downstream target of GPR40, which regulates cortical actin remodelling and amplifies the second phase of insulin secretion in response to fatty acids. We have also observed that glucose regulates the expression of the gene encoding GPR40 via a transcriptional mechanism that involves O-GlcNAcylation of the transcription factor pancreas-duodenum homeobox-1 and requires activity of phosphatidylinositol-3-kinase. These recent studies provide important mechanistic information as GPR40 agonists are being developed as new type 2 diabetes drugs; however, many questions remain to be answered regarding the biology of this receptor and its potential role in tissues other than the β-cell.