[HTML][HTML] G protein-coupled receptor (GPR) 40-dependent potentiation of insulin secretion in mouse islets is mediated by protein kinase D1
M Ferdaoussi, V Bergeron, B Zarrouki, J Kolic… - Diabetologia, 2012 - Springer
Diabetologia, 2012•Springer
Aims/hypothesis Activation of the G protein-coupled receptor (GPR) 40 by long-chain fatty
acids potentiates glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells, and
GPR40 agonists are in clinical development for type 2 diabetes therapy. GPR40 couples to
the G protein subunit Gα q/11 but the signalling cascade activated downstream is unknown.
This study aimed to determine the mechanisms of GPR40-dependent potentiation of GSIS
by fatty acids. Methods Insulin secretion in response to glucose, oleate or diacylglycerol …
acids potentiates glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells, and
GPR40 agonists are in clinical development for type 2 diabetes therapy. GPR40 couples to
the G protein subunit Gα q/11 but the signalling cascade activated downstream is unknown.
This study aimed to determine the mechanisms of GPR40-dependent potentiation of GSIS
by fatty acids. Methods Insulin secretion in response to glucose, oleate or diacylglycerol …
Aims/hypothesis
Activation of the G protein-coupled receptor (GPR)40 by long-chain fatty acids potentiates glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells, and GPR40 agonists are in clinical development for type 2 diabetes therapy. GPR40 couples to the G protein subunit Gαq/11 but the signalling cascade activated downstream is unknown. This study aimed to determine the mechanisms of GPR40-dependent potentiation of GSIS by fatty acids.
Methods
Insulin secretion in response to glucose, oleate or diacylglycerol (DAG) was assessed in dynamic perifusions and static incubations in islets from wild-type (WT) and Gpr40 −/− mice. Depolymerisation of filamentous actin (F-actin) was visualised by phalloidin staining and epifluorescence. Pharmacological and molecular approaches were used to ascertain the roles of protein kinase D (PKD) and protein kinase C delta in GPR40-mediated potentiation of GSIS.
Results
Oleate potentiates the second phase of GSIS, and this effect is largely dependent upon GPR40. Accordingly, oleate induces rapid F-actin remodelling in WT but not in Gpr40 −/− islets. Exogenous DAG potentiates GSIS in both WT and Gpr40 −/− islets. Oleate induces PKD phosphorylation at residues Ser-744/748 and Ser-916 in WT but not Gpr40 −/− islets. Importantly, oleate-induced F-actin depolymerisation and potentiation of GSIS are lost upon pharmacological inhibition of PKD1 or deletion of Prkd1.
Conclusions/interpretation
We conclude that the signalling cascade downstream of GPR40 activation by fatty acids involves activation of PKD1, F-actin depolymerisation and potentiation of second-phase insulin secretion. These results provide important information on the mechanisms of action of GPR40, a novel drug target for type 2 diabetes.
Springer