G protein-coupled receptor (GPR)40-dependent potentiation of insulin secretion in mouse islets is mediated by protein kinase D1

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Item Type:	Article
Title:	G protein-coupled receptor (GPR)40-dependent potentiation of insulin secretion in mouse islets is mediated by protein kinase D1
Creators Name:	Ferdaoussi, M., Bergeron, V., Zarrouki, B., Kolic, J., Cantley, J., Fielitz, J., Olson, E.N., Prentki, M., Biden, T., Macdonald, P.E. and Poitout, V.
Abstract:	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 Galpha(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 (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.
Keywords:	Diacylglycerol, Filamentous Actin, G Proteincoupled Receptor, GPR40, Insulin Secretion, Islet, Protein Kinase D, Type 2 Diabetes, Animals, Mice
Source:	Diabetologia
ISSN:	0012-186X
Publisher:	Springer
Volume:	55
Number:	10
Page Range:	2682-2692
Date:	October 2012
Official Publication:	https://doi.org/10.1007/s00125-012-2650-x
PubMed:	View item in PubMed

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