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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.”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [618]
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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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Items 101–187 of 187
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BackgroundSelf-citationPancreas and Not Gut Mediates the GLP-1-Induced Glucoincretin Effect
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“, by using a variety of methods including the use of 9-phenanthrol, have demonstrated that TRPM4 is involved in the GLP-1-induced insulin secretion from mouse islets [10].”
MethodZhang, Y., Li, M., Wang, Y., Liu, X., Zhou, L., Zhang, C., & Shao, L. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.118073 · Cited by 13
New concept of the glucagon‐like peptide‐1 signaling pathway on pancreatic insulin secretion
Kaku, K. (2019) · Journal of Diabetes Investigation · doi:10.1111/jdi.13136 · Cited by 13
“The recent study reported by Shigeto et al.5 has made the possibility real.”
BackgroundInfluentialSelf-citationThe Role of TRP Channels in the Pancreatic Beta-Cell
Philippaert, K., & Vennekens, R. (2017) · CRC Press eBooks · doi:10.4324/9781315152837-12 · Cited by 13
Self-citationNew prospects for incretin‐related drugs in the treatment of type 2 diabetes
Kimura, T., & Kaku, K. (2020) · Journal of Diabetes Investigation · doi:10.1111/jdi.13460 · Cited by 12
Self-citationGLP-1 and Its Role in Glycogen Production: A Narrative Review
Lotosky, J., Jean, X., Altankhuyag, A., Khan, S. R., Bernotas, A., Sharafshah, A., Blum, K., Posner, A. R., & Thanos, P. K. (2025) · Biomedicines · doi:10.3390/biomedicines13071610 · Cited by 14
“Picomolar concentrations of GLP-1 activate PKC and increase insulin secretion in mouse islet cells independent of protein kinase A (PKA) activation [75].”
Liu, C., Liu, W.-H., Yang, W., Chen, L., Xue, Y., & Chen, X. (2024) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.109946 · Cited by 11
“It is reported that knockout of TRP mela-statin (TRPM) Trpm4 or Trpm5 blocks GLP-1-induced depolarization and increase in action potential frequency in pancreatic islets (Shigeto et al., 2015).”
The regulation of insulin secretion via phosphoinositide-specific phospholipase Cβ signaling
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“While GLP-1 has been shown to regulate the phosphatidylinositol-phospholipase C (PI-PLC) or phosphatidylcholine-phospholipase C (PC-PLC) activity in mouse pancreatic b cells [56], experiments with the PIPLC inhibitor U73122 or with the PC-PLC inhibitor D609, did not support the involvement of these two pathways in”
BackgroundResultTRPM3, TRPM4, and TRPM5 as thermo-sensitive channels
Uchida, K. (2024) · The Journal of Physiological Sciences · doi:10.1186/s12576-024-00937-0 · Cited by 11
“The Ca 2 + sensitivity of TRPM4 is also regulated by PKC-dependent phosphorylation [49, 62].”
BackgroundClassical and non-classical islet peptides in the control of β-cell function
Khan, D., Moffett, R. C., Flatt, P. R., & Tarasov, A. I. (2021) · Peptides · doi:10.1016/j.peptides.2021.170715 · Cited by 10
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“We propose that GLP-1(7-36) and GLP-1(9-36)”
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“There is evidence of the participation of PKC signaling in insulin secretion, that GLP-1-activated PKCs may contribute to insulin secretion INS-1 cells [59] and pancreatic islets [60,61].”
BackgroundDuodenal chemosensory system: enterocytes, enteroendocrine cells, and tuft cells
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“Shigeto M, Ramracheya R, Tarasov AI, et al. GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation.”
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“In these experiments, 2 different concentrations of GLP-1, 10 and 300 pM, were used since it has been reported previously that 10 pM GLP-1 stimulates insulin secretion through a G α q/PLC/Ca 2+ pathway, while 300 pM GLP-1 engages G α s/cAMP/PKA (20).”
InfluentialReceptor activity–modifying protein 3 enhances GLP-1-mediated insulin secretion
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“Previous studies have shown potentiation of GSIS to be both PKA dependent (36) and independent (37), with this study agreeing with the latter, although this might be due to reduced affinity of the compound for the rat kinases.”
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“Expression of recombinant probes can be induced in the endocrine pancreas using adenoviral or baculovirus vectors (380, 381).”
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Pyruvate kinase modulates the link between β‐cell fructose metabolism and insulin secretion
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“40,41 Importantly, these effects become substantial only when the conductance of β - cell membranes is already reduced owing to K ATP channel closure.”
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“In both mouse and human beta cells, the ability of GLP-1 to induce membrane depolarisation and initiate action potential firing depend on extracellular Na + and TRPM5 activity [23, 29, 30].”
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Self-citationTRPM5 activation depends on a synergistic effect of calcium and PKC phosphorylation
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“Phosphorylation by protein kinase C (PKC) is an essential aspect of TRPM channel regulation, encompassing TRPM4 and TRPM5 45 , and has functional implications in various cellular contexts.”
BackgroundGLP-1/GLP-1RAs: New Options for the Drug Treatment of NAFLD
Jiang, H., & Zang, L. (2024) · Current Pharmaceutical Design · doi:10.2174/0113816128283153231226103218 · Cited by 6
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“…glucose is low or absent (38, 43, 52, 66, 116), subthreshold glucose levels are suf fi cient for inducing membrane depolarization (52, 60, 62, 65, 66, 110, 117) and [Ca 2+ ] IC increases (43, 48, 52, 66, 70, 116 – 118) in at least a part of islet beta cells and that this activity resembles…”
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“TRPM5 functions downstream of Gαq-or gustducin-coupled GPCR signaling cascades, wherein PLCβ activation triggers Ca 2+ release from the IP 3 receptor and protein kinase C (PKC) activation, both of which facilitate TRPM5 gating [62].”
Gilijamse, P. W., Demirkıran, A., van Wagensveld, B. A., Ackermans, M. T., Romijn, J. A., Nieuwdorp, M., ter Horst, K. W., & Serlie, M. J. M. (2021) · Surgery for Obesity and Related Diseases · doi:10.1016/j.soard.2021.04.022 · Cited by 4
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“Trigonelline also reduces the rate of beta cell apoptosis (Shigeto et al. 2015; Yeung et al. 2022), and thus makes the islets enormously enlarged.”
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“Sodium entry through Na v and TRPM4/5 channels contributes to β -cell V m depolarization during glucose-stimulated Ca 2 + oscillations [68,69], and subsequent NKA activation serves as the primary mechanism for clearing accumulated Na + , facilitating V m hyperpolarization and termination of Ca 2 +…”
Zhang, F., Chen, W., Wang, H., Wu, D., Chen, Z., Cheng, R., Hu, J., Xie, L., Qiu, Y., Zhou, Z., et al. (2026) · Journal of Advanced Research · doi:10.1016/j.jare.2026.02.006 · Cited by 1
Acute Contractile Effects of Glucagon-like-Peptide-1 Receptor Agonists in the Human Heart
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“In contrast, lower, physiological (picomolar) concentrations of GLP-1 appear to work via PLC-mediated pathways [60] acting by protein kinase C via inositol-triphosphate-induced Ca 2+ release and the activation of the L-type calcium ion channel in non-cardiac cells [61].”
Lallouet, M., Jaffredo, M., Pirog, A., Leal-Fischer, K., Gaitan, J., Meier, D. T., Renaud, S., Raoux, M., & Lang, J. (2026) · Science Advances · doi:10.1126/sciadv.aea9045 · Cited by 1
“Whereas glucagon can activate both glucagon and GLP-1 receptors, GLP-1 is specific and far more potent for its cognate receptor ( 10 ).”
Insufficient TRPM5 Mediates Lipotoxicity-induced Pancreatic β-cell Dysfunction
Wang, K., Wu, S.-M., Yao, Z.-J., Zhu, Y., & Han, X. (2024) · Current Medical Science · doi:10.1007/s11596-023-2795-5 · Cited by 1
“In pancreatic β cells, Ca 2+ -activated non-selective cation channels have been reported to be stimulated in both human and rodent β cells [39, 40] , and the deletion of Trpm5 in mice leads to glucose intolerance due to GSIS defects [8] .”
Cholecystokinin knockout mice: peripheral and central phenotypes
Lo, C. C., Black, D. D., & Tso, P. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-23720-1.00021-6 · Cited by 1
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“Recently, it has been reported that GLP-1 can activate PLC and elevate cytosolic IP3 independently of cAMP by interacting with a G protein of the Gαq family (80, 88).”
BackgroundPang, H., Wang, X., Xi, W., Zhao, Q., Zhang, S., Qin, J., Lv, J., Che, Y., Zuo, W., & Li, S. J. (2017) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/097816
“the activation of PKC results in membrane depolarization, Ca 2+ influx and then priming of insulin secretion (33).”
BackgroundNew insights into KATP channel gene mutations and neonatal diabetes mellitus
Pipatpolkai, T., Usher, S., Stansfeld, P. J., & Ashcroft, F. (2020) · Yearbook of pediatric endocrinology · doi:10.1530/ey.17.2.13
Gemcitabine Resistance Elicits a Calcium Dependent Epigenetic Reprogramming in Pancreatic Cancer
Kutschat, A. P. (2021) · eDiss (Georg-August-Universität Göttingen) · doi:10.53846/goediss-8475
Redox Signaling is Essential for Insulin Secretion
Ježek, P., Holendová, B., Jabůrek, M., Tauber, J. A., Dlasková, A., & Plecitá‐Hlavatá, L. (2021) · IntechOpen eBooks · doi:10.5772/intechopen.94312
Accompagner une personne polyhandicapée au domicile
Delbos, R., & Issartel, D. (2010) · La Revue de l Infirmière
Targeting Islet GPCRs to Improve Insulin Secretion
Atanes, P., Ruz‐Maldonado, I., & Persaud, S. J. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-820472-6.00050-5 · Cited by 1
Guinamard, R., Simard, C., & Sallé, L. (2017) · Springer eBooks · doi:10.1007/978-3-319-67199-4_101882
Guinamard, R., Simard, C., & Sallé, L. (2016) · Springer eBooks · doi:10.1007/978-1-4614-6438-9_101882-1
A Surge of Extracellular Succinate Ensures Glucose Supply During Systemic High Energy DemandPreprint
Wu, Y., Andersson-Hall, U. K., Dou, H., Shrestha, M. M., Komai, A. M., Tolö, J., Pettersson, S., Pedersen, A., Chanclón, B., Bauzá-Thorbrügge, M., et al. (2022) · SSRN Electronic Journal · doi:10.2139/ssrn.4099800
Self-citationIncretin Therapies: Current Use and Emerging Possibilities
Schlögl, H., & Stümvoll, M. (2023) · Springer eBooks · doi:10.1007/978-3-031-25519-9_35
Bonner, C., Saponaro, C., Imbernón, M., Louvet, I., Deligia, E., Chen, S., Davies, I., Acosta-Montalvo, A., Moreno-Lopez, M., Wemelle, E., et al. (2024) · Research Square · doi:10.21203/rs.3.rs-5544620/v1
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Birth of a Microdomain: Can Glucose Act as a Metabolic Switch?
Pallavi, A., & Gandasi, N. R. (2025) · DNA and Cell Biology · doi:10.1177/10445498251391706
“…ATP, which can mobilize intracellular Ca2 + reserves through purinergic P2Y receptors (Drucker et al., 1987; Gucek et al., 2019; Jones et al., 2018; McIntosh et al., 2012; Petersen et al., 2015; Seino et al., 2010; Shibasaki et al., 2007; Shigeto et al., 2015; Tengholm, 2012; Xie et al., 2006).”
Structural insights into Phospholipase Cε activity and regulation
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Protein kinase C in neurodegenerative disorders
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Saponaro, C., Imbernón, M., Louvet, I., Deligia, E., Chen, S., Davies, I., Acosta-Montalvo, A., Moreno-Lopez, M., Wemelle, E., Kothegala, L., et al. (2026) · Diabetologia · doi:10.1007/s00125-026-06779-2
“To understand liraglutide’s lack of efficacy under nor-moglycaemic conditions, we investigated GLP-1R-mediated intracellular Ca 2+ mobilisation, a critical mediator of insulin granule exocytosis and GLP-1R signalling [38–40].”
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Obesity and Atrial Fibrillation: Weighing the Evidence
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“GLP-1 RAs increase insulin secretion in a glucose-dependent manner [80,81], slow gastric emptying [80,82,83], reduce appetite and promote satiety [84,85].”
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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