ArticleDiabetologia2012
G protein-coupled receptor (GPR)40-dependent potentiation of insulin secretion in mouse islets is mediated by protein kinase D1.
Article in Diabetologia, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 82 papers.
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Who cites it
82 citing papers in PubMed, 156 citations in OpenAlex.
- Nutrient and non-nutrient regulators of insulin secretion.Nature reviews. Endocrinology · 2026Review
- The roles of free-fatty acid receptors in the pathophysiology of renal disorders.The Journal of pharmacology and experimental therapeutics · 2026Review
- GPR40 activation alleviates pulmonary fibrosis by repressing M2 macrophage polarization through the PKD1/CD36/TGF-β1 pathway.Acta pharmacologica Sinica · 2025Article
- Review
- Proteomic predictors of individualized nutrient-specific insulin secretion in health and disease.Cell metabolism · 2024Article
- The Role of G Protein-Coupled Receptors and Receptor Kinases in PancreaticPharmacological reviews · 2024Review
- Protein kinase D1 - A targetable mediator of pancreatic cancer development.Biochimica et biophysica acta. Molecular cell research · 2024Review
- Recent Developments in Drug Design of Oral Synthetic Free Fatty Acid Receptor 1 Agonists.Drug design, development and therapy · 2024Review
- Metabolic and Molecular Amplification of Insulin Secretion.Advances in anatomy, embryology, and cell biology · 2024Review
- Platelet-derived lipids promote insulin secretion of pancreatic β cells.EMBO molecular medicine · 2023Article
- Metabolic regulation of glucagon secretion.The Journal of endocrinology · 2023Article
- CaBiomedicines · 2023Review
- β-cell dynamics in type 2 diabetes and in dietary and exercise interventions.Journal of molecular cell biology · 2022Review
- The Liver-α-Cell Axis in Health and in Disease.Diabetes · 2022Review
- The role of free fatty acid receptor pathways in a selective regulation of TRPA1 and TRPV1 by resolvins in primary sensory neurons.Journal of cellular physiology · 2022Article
- Contribution of Mitochondria to Insulin Secretion by Various Secretagogues.Antioxidants & redox signaling · 2022Review
- Loss and Recovery of Glutaredoxin 5 Is Inducible by Diet in a Murine Model of Diabesity and Mediated by Free Fatty Acids In Vitro.Antioxidants (Basel, Switzerland) · 2022Article
- A FFAR1 full agonist restores islet function in models of impaired glucose-stimulated insulin secretion and diabetic non-human primates.Frontiers in endocrinology · 2022Article
- Pharmacogenetics of new classes of antidiabetic drugs.Bosnian journal of basic medical sciences · 2021Review
- β-Cell Knockout of SENP1 Reduces Responses to Incretins and Worsens Oral Glucose Tolerance in High-Fat Diet-Fed Mice.Diabetes · 2021Article
22 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 6 institutions in 4 countries.
Funding
Abstract
aims/hypothesisActivation 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.
methodsInsulin 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.
resultsOleate 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/
interpretationWe 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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