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, J. Cantley, J. Fielitz, E. N. Olson, M. Prentki, T. Biden, P. E. MacDonald, V. Poitout

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish (US)
Pages (from-to)2682-2692
Number of pages11
JournalDiabetologia
Volume55
Issue number10
DOIs
StatePublished - Oct 2012

Fingerprint

G-Protein-Coupled Receptors
Protein Kinases
Insulin
Oleic Acid
Glucose
Actins
Fatty Acids
Diglycerides
Type 2 Diabetes Mellitus
Pharmacology
Protein Kinase C-delta
Phalloidine
Protein Subunits
Insulin-Secreting Cells
GTP-Binding Proteins
Phosphorylation
Staining and Labeling
Pharmaceutical Preparations

Keywords

  • Diacylglycerol
  • Filamentous actin
  • G protein-coupled receptor
  • GPR40
  • Insulin secretion
  • Islet
  • Protein kinase D
  • Type 2 diabetes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Ferdaoussi, M., Bergeron, V., Zarrouki, B., Kolic, J., Cantley, J., Fielitz, J., ... Poitout, V. (2012). G protein-coupled receptor (GPR)40-dependent potentiation of insulin secretion in mouse islets is mediated by protein kinase D1. Diabetologia, 55(10), 2682-2692. https://doi.org/10.1007/s00125-012-2650-x

G protein-coupled receptor (GPR)40-dependent potentiation of insulin secretion in mouse islets is mediated by protein kinase D1. / Ferdaoussi, M.; Bergeron, V.; Zarrouki, B.; Kolic, J.; Cantley, J.; Fielitz, J.; Olson, E. N.; Prentki, M.; Biden, T.; MacDonald, P. E.; Poitout, V.

In: Diabetologia, Vol. 55, No. 10, 10.2012, p. 2682-2692.

Research output: Contribution to journalArticle

Ferdaoussi, M, Bergeron, V, Zarrouki, B, Kolic, J, Cantley, J, Fielitz, J, Olson, EN, Prentki, M, Biden, T, MacDonald, PE & Poitout, V 2012, 'G protein-coupled receptor (GPR)40-dependent potentiation of insulin secretion in mouse islets is mediated by protein kinase D1', Diabetologia, vol. 55, no. 10, pp. 2682-2692. https://doi.org/10.1007/s00125-012-2650-x
Ferdaoussi, M. ; Bergeron, V. ; Zarrouki, B. ; Kolic, J. ; Cantley, J. ; Fielitz, J. ; Olson, E. N. ; Prentki, M. ; Biden, T. ; MacDonald, P. E. ; Poitout, V. / G protein-coupled receptor (GPR)40-dependent potentiation of insulin secretion in mouse islets is mediated by protein kinase D1. In: Diabetologia. 2012 ; Vol. 55, No. 10. pp. 2682-2692.
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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 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.",
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AU - Ferdaoussi, M.

AU - Bergeron, V.

AU - Zarrouki, B.

AU - Kolic, J.

AU - Cantley, J.

AU - Fielitz, J.

AU - Olson, E. N.

AU - Prentki, M.

AU - Biden, T.

AU - MacDonald, P. E.

AU - Poitout, V.

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N2 - 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.

AB - 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.

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KW - Filamentous actin

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KW - Islet

KW - Protein kinase D

KW - Type 2 diabetes

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