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

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/1...

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Published in:Diabetologia 2012-10, Vol.55 (10), p.2682-2692
Main Authors: Ferdaoussi, M., Bergeron, V., Zarrouki, B., Kolic, J., Cantley, J., Fielitz, J., Olson, E. N., Prentki, M., Biden, T., MacDonald, P. E., Poitout, V.
Format: Article
Language:English
Subjects:
Actins - metabolism
Animals
Cells, Cultured
Diabetes
Diglycerides - pharmacology
Fatty acids
Glucose
Glucose - pharmacology
Human Physiology
Insulin - metabolism
Insulin resistance
Insulin Secretion
Internal Medicine
Islets of Langerhans - cytology
Islets of Langerhans - drug effects
Islets of Langerhans - metabolism
Kinases
Medicine
Medicine & Public Health
Metabolic Diseases
Mice
Mice, Knockout
Models, Animal
Oleic Acid - pharmacology
Protein Kinase C - physiology
Protein Kinase C-delta - deficiency
Protein Kinase C-delta - genetics
Protein Kinase C-delta - physiology
Proteins
Receptors, G-Protein-Coupled - deficiency
Receptors, G-Protein-Coupled - genetics
Receptors, G-Protein-Coupled - physiology
Signal Transduction - physiology
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Summary: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 (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.
ISSN:0012-186X
1432-0428
DOI:10.1007/s00125-012-2650-x