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GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation
Open accessAbstract
Strategies aimed at mimicking or enhancing the action of the incretin hormone glucagon-like peptide 1 (GLP-1) therapeutically improve glucose-stimulated insulin secretion (GSIS); however, it is not clear whether GLP-1 directly drives insulin secretion in pancreatic islets. Here, we examined the mechanisms by which GLP-1 stimulates insulin secretion in mouse and human islets. We found that GLP-1 enhances GSIS at a half-maximal effective concentration of 0.4 pM. Moreover, we determined that GLP-1 activates PLC, which increases submembrane diacylglycerol and thereby activates PKC, resulting in membrane depolarization and increased action potential firing and subsequent stimulation of insulin secretion. The depolarizing effect of GLP-1 on electrical activity was mimicked by the PKC activator PMA, occurred without activation of PKA, and persisted in the presence of PKA inhibitors, the KATP channel blocker tolbutamide, and the L-type Ca(2+) channel blocker isradipine; however, depolarization was abolished by lowering extracellular Na(+). The PKC-dependent effect of GLP-1 on membrane potential and electrical activity was mediated by activation of Na(+)-permeable TRPM4 and TRPM5 channels by mobilization of intracellular Ca(2+) from thapsigargin-sensitive Ca(2+) stores. Concordantly, GLP-1 effects were negligible in Trpm4 or Trpm5 KO islets. These data provide important insight into the therapeutic action of GLP-1 and suggest that circulating levels of this hormone directly stimulate insulin secretion by β cells.
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“As in mouse islets, glucose and sulfonylureas (618) are true initiators of electrical activity in human β-cells.”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [618]
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“The fact that removal of extracellular Na+ does not prevent glucose-induced depolarization (549, 618) argues that the current cannot be Na+-dependent.”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [618]
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“which suggests two-pore channels may not play an important role in glucose-induced electrical activity, at least in mouse β-cells.”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [618]
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“However, GIIS is little affected in Tpcn1/Tpcn2 double knockout mice (618), which suggests two-pore channels may not play an important role in glucose-induced electrical activity, at least in mouse β-cells.”
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“Amino acids (arginine and glycine)(744), neurotransmitters (like adenine nucleotides, GABA and acetylcholine) (89, 92, 347, 568) and hormones (618) can also stimulate electrical activity and insulin release but only in the presence of a ‘permissive’ concentration of glucose.”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [618]
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“Membrane depolarization by GLP-1 was mimicked by the PKC activator phorbol myristate acetate (PMA) and was not affected by treatment with either the PKA inhibitor myr-PKI, the KATP channel blocker tolbutamide, or the L-type Ca2þ channel inhibitor isradipine [514].”
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“The GLP-1 receptor also appears to couple via Gαq to stimulate phospholipase C, which generates Ca-mobilizing inositol-1,4,5 trisphosphate (IP3) and protein kinase C (PKC)-activating diacylglycerol.(53) PKC in turn depolarizes the β-cells by activating Na influx through TRPM4 and TRPM5 channels to promote voltage-depe…”
Background
Metadata
- Authors
- Shigeto, M., Ramracheya, R., Tarasov, A. I., Cha, C. Y., Chibalina, M. V., Hastoy, B., Philippaert, K., Reinbothe, T., Rorsman, N., Salehi, A., Sones, W. R., Vergari, E., Weston, C., Gorelik, J., Katsura, M., Nikolaev, V. O., Vennekens, R., Zaccolo, M., Galione, A., Johnson, P. R. V., Kaku, K., Ladds, G., & Rorsman, P.
- Affiliations
- Kawasaki Medical School (JP)
- Churchill Hospital (GB)
- KU Leuven (BE)
- University of Gothenburg (SE)
- University of Warwick (GB)
- Imperial College London (GB)
- Universität Hamburg (DE)
- University of Oxford (GB)
- University of Cambridge (GB)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2015-11-16
- Volume
- 125
- Issue
- 12
- Pages
- 4714-4728
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC4665783
- OpenAlex
- W2178272961
- Cited by
- 189
- References
- 66
- Citations by year
- 2026: 10 · 2025: 18 · 2024: 21 · 2023: 8 · 2022: 15 · 2021: 26 · 2020: 23 · 2019: 14 · 2018: 16 · 2017: 26 · 2016: 10 · 2015: 1
- FWCI
- 17.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- University of Hertfordshire Research Archive (University of Hertfordshire) (acceptedVersion)
- University of Hertfordshire Research Archive (University of Hertfordshire) (submittedVersion)
- Lirias (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Funders
- Impact Fund
- Wellcome Trust (102828, 084655, 095531/Z/11/Z, 102828/Z/13/Z, 095531)
- British Heart Foundation (RG/12/3/29423)
- Diabetes UK
- University of Warwick
- University of Oxford
- KU Leuven
- Knut och Alice Wallenbergs Stiftelse
- Vetenskapsrådet
- Kawasaki Medical School
- Directorate for Biological Sciences
- Medical Research Council
- Biotechnology and Biological Sciences Research Council (BB/M00015X/1, BB/M00015X/2)
- Japan Society for the Promotion of Science (25460113)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- glucagon-like peptide-1, insulin secretion, glucose-stimulated insulin secretion, pancreatic beta cells, TRPM4, TRPM5, protein kinase C, diacylglycerol, phospholipase C, membrane depolarization, action potential firing, sodium channels, intracellular calcium stores, incretin-based therapy
- MeSH terms
- Insulin Secretion, Animals, Humans, Insulin, Membrane Potentials, Protein Kinase C, Tetradecanoylphorbol Acetate, Ion Transport, Mice, Knockout, TRPM Cation Channels, Insulin-Secreting Cells, Mice, Glucagon-Like Peptide 1
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