Potentiation of Glucose-stimulated Insulin Secretion by the GPR40–PLC–TRPC Pathway in Pancreatic β-Cells
Open accessAbstract
G protein-coupled receptors (GPCRs) are expressed in pancreatic beta-cells. G protein-coupled receptor 40 (GPR40) contributes to medium- or long-chain fatty acid-induced amplification of glucose-stimulated insulin secretion (GSIS) and GPR40 agonists are promising therapeutic targets in type 2 diabetes. Recently, we demonstrated that glucagon-like peptide 1, a ligand of pancreatic GPCR, activates a class of nonselective cation channels (NSCCs) and enhances GSIS. The aim of the current study was to determine whether the GPR40 signal interacts with NSCCs. A GPR40 agonist (fasiglifam) potentiated GSIS at 8.3 and 16.7 mM glucose but not 2.8 mM glucose. The NSCC current was activated by fasiglifam at 5.6 mM glucose with 100 μM tolbutamide (−70 mV) and this activation was prevented by the presence of pyrazole-3 (transient receptor potential canonical; a TRPC3 channel blocker). Inhibitors of phospholipase C or protein kinase C (PKC) inhibited the increases in GSIS and the NSCC current induced by GPR40 stimulation. The present study demonstrates a novel mechanism for the regulation of insulin secretion by GPR40 agonist in pancreatic beta-cells. The stimulation of the GPR40–PLC/PKC–TRPC3 channel pathway potentiates GSIS by the depolarization of the plasma membrane in pancreatic beta-cell.
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The GPR40 agonist fasiglifam activates a small inward current in the presence of glucose and tolbutamide (~1 pA/pF at -70 mV).
“More recently, the GPR40 agonist fasiglifam was shown to activate a small inward current in the presence of glucose and tolbutamide (~1 pA/pF at -70 mV) (743).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [743]
The Results section (‘Fasiglifam, a GPR40 agonist…’; Fig. 1a,b) reports that fasiglifam increased an inward current in beta-cells held at −70 mV with 5.6 mM glucose and tolbutamide present. The passages in our copy do not give the claimed magnitude of approximately 1 pA/pF, so that numerical detail is unverified. (LLM, conf=0.86)
Experimental — accuracy not yet measuredFasiglifam activation of the inward current is associated with ~15 mV depolarization and moderate stimulation of insulin secretion at both 8.3 and 16.7 mM glucose.
“This was associated with an ~15 mV depolarization and a moderate stimulation of insulin secretion at both 8.3 and 16.7 mM glucose.”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [743]
The stimulatory effect of fasiglifam can be antagonized by the TRPC3 channel-specific blocker pyrazole-3.
“The stimulatory effect of the fasiglifam could be antagonized by the TRPC3 channel-specific blocker pyrazole-3 (743).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [743]
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- Authors
- Yamada, H., Yoshida, M., Ito, K., Dezaki, K., Yada, T., Ishikawa, S.-E., & Kakei, M.
- Affiliations
- Jichi Medical University Saitama Medical Center (JP)
- Jichi Medical University (JP)
- Corresponding author
- Kakei, Masafumi
- Venue
- Scientific Reports
- Published
- 2016-05-16
- Volume
- 6
- Issue
- 1
- Pages
- 25912-25912
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC4867641
- OpenAlex
- W2397497372
- Cited by
- 81
- References
- 34
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 9 · 2023: 2 · 2022: 4 · 2021: 15 · 2020: 6 · 2019: 10 · 2018: 8 · 2017: 12 · 2016: 4
- FWCI
- 12.54
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Jichi Medical University
- Japan Society for the Promotion of Science (16K19545, 15K09397, 15K09396, 26670453, 26870532)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Keywords
- GPR40, glucose-stimulated insulin secretion, pancreatic beta cells, phospholipase C, protein kinase C, TRPC3 channels, non-selective cation channels, glucagon-like peptide-1, type 2 diabetes, membrane depolarization, fatty acid signaling
- MeSH terms
- Insulin Secretion, Animals, Benzofurans, Drug Synergism, Glucose, Insulin, Male, Type C Phospholipases, Sulfones, Tolbutamide, Signal Transduction, Receptors, G-Protein-Coupled, TRPC Cation Channels, Insulin-Secreting Cells, Rats
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