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GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation
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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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Glucagon-like peptide 1 (GLP-1)
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“GLP-1 is also categorized as an incretin hormone due to its role in postprandial glucose clearance, by facilitating insulin secretion from pancreatic beta cells.(37) In addition, GLP-1 stimulates brown adipose tissue (BAT) thermogenesis via activation of the AMPK pathway, thereby increasing energy expenditure.”
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“There is more evidence that GLP-1R can couple to Gaq in beta cells, as demonstrated by inositol triphosphate (IP3) turnover studies (39), diacylglycerol (DAG) production (40) and most convincingly, a Gaq FRET biosensor (41).”
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“This contributes to further inhibition of the KATP channels (65) and activation of a depolarizing background conductance (41), leading to sustained elevation of [Ca]i.”
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“However, the exact Ca2+ binding sites on TRPM5 have not yet been identified.”
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“In the latter study, both efficacy and potency were higher for Gαs than for Gαq, with some evidence of coupling to Gαi also demonstrated.”
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InfluentialSelf-citationTRPM5 in the battle against diabetes and obesity
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“On the other hand, a recent study suggested that part of the insulin release stimulating effect of GLP-1 on pancreatic b-cells might be mediated via activation of TRPM5 and/or TRPM4.(96) These results suggest that TRPM5 potentiating compounds, such as stevioside,”
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“PKC phosphorylation enhances the sensitivity of the TRPM4 for activation by Ca2+.”
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“…The potential effects of both glucagon and GLP1 on insulin secretion either in isolated islets ex vivo or in mice and humans in vivo are glucose-concentration dependent, [26] and deciphering their relative contributions to the regulation of insulin secretion is an ongoing line of investigation.”
BackgroundDynamic Uni- and Multicellular Patterns Encode Biphasic Activity in Pancreatic Islets
Jaffredo, M., Bertin, É., Pirog, A., Puginier, E., Gaitan, J., Ouchérif, S., Lebreton, F., Bosco, D., Catargi, B., Cattaert, D., et al. (2021) · Diabetes · doi:10.2337/db20-0214 · Cited by 32
Sabadell‐Basallote, J., Astiarraga, B., Castaño, C., Ejarque, M., Repollés-de-Dalmau, M., Quesada, I., Blanco, J., Núñez‐Roa, C., Rodríguez‐Peña, M., Martínez, L., et al. (2024) · Journal of Clinical Investigation · doi:10.1172/jci173214 · Cited by 32
“Within the framework of neurohormonal amplification pathways, PKC activation is almost universally accepted as a major mechanism of GPCR-stimulated insulin secretion (55, 56).”
BackgroundContribution of Mitochondria to Insulin Secretion by Various Secretagogues
Ježek, P., Holendová, B., Jabůrek, M., Dlasková, A., & Plecitá‐Hlavatá, L. (2021) · Antioxidants and Redox Signaling · doi:10.1089/ars.2021.0113 · Cited by 33
“The major axis involves the phosphorylation of TRPM4 (TRPM5) channels by PKC activated by DAG (231) or TRPC3 activation (276).”
BackgroundInfluentialDienes, C., Kovács, Z. M., Hézső, T., Almássy, J., Magyar, J., Bányász, T., Nánási, P. P., Horváth, B., & Szentandrássy, N. (2021) · Pharmaceuticals · doi:10.3390/ph15010040 · Cited by 32
“Similarly, GLP-1-induced insulin secretion— mediated by Protein Kinase C (PKC) and the mobilization of intracellular Ca2+ from thapsigargin-sensitive Ca2+ stores—involved TRPM4 activation, as it was negligible in the TRPM4 knock-out (KO) mice [49].”
BackgroundWang, D., Jiang, L., Feng, B., He, N., Zhang, Y., & Ye, H. (2019) · Journal of Diabetes Investigation · doi:10.1111/jdi.13098 · Cited by 30
Feng, J., Kang, C., Wang, C., Ding, L., Zhu, W., & Hang, S. (2019) · Animals · doi:10.3390/ani9080476 · Cited by 31
“A previous study shows how the activation of PKC stimulated GLP-1-induced insulin secretion in mouse and human islets [17].”
BackgroundPark, S., Kang, S., & Kim, D. S. (2019) · Nutrition Research · doi:10.1016/j.nutres.2019.09.008 · Cited by 31
Ito, K., Dezaki, K., Yoshida, M., Yamada, H., Miura, R., Rita, R. S., Ookawara, S., Tabei, K., Kawakami, M., Hara, K., et al. (2016) · Diabetes · doi:10.2337/db16-1166 · Cited by 31
Unlocking the multifaceted roles of GLP-1: Physiological functions and therapeutic potential
AL-Noshokaty, T. M., Abdelhamid, R., Abdelmaksoud, N. M., Khaled, A., Hossam, M., Ahmed, R., Saber, T., Khaled, S., Elshaer, S. S., & Abulsoud, A. I. (2025) · Toxicology Reports · doi:10.1016/j.toxrep.2025.101895 · Cited by 30
“…of GLP-1 through mechanisms that are dependent on PKC. GLP-1 ’ s capacity to induce phosphorylation in a PKC-dependent manner and the fact that the PKC activator can reproduce its effect on β cell electrical activity provide evidence that PKC is involved in GLP-1 ’ s stimulatory function [82].”
Toward Connecting Metabolism to the Exocytotic Site
Ferdaoussi, M., & MacDonald, P. E. (2016) · Trends in Cell Biology · doi:10.1016/j.tcb.2016.10.003 · Cited by 32
Voets, T., Vriens, J., & Vennekens, R. (2019) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2019.07.004 · Cited by 28
Self-citationZhang, Q., Dou, H., & Rorsman, P. (2020) · The Journal of Physiology · doi:10.1113/jp279775 · Cited by 31
“J Physiol 598.21 KATP channels in pancreatic α- and β-cells 4769 tolbutamide have (unlike what is seen in control islets) little or no further glucagonostatic effect (Gromada et al. 2004; Munoz et al. 2005; Shiota et al. 2005; MacDonald et al. 2007; Cheng-Xue et al. 2013).”
BackgroundInfluentialSelf-citationBos, R., Drouillas, B., Bouhadfane, M., Pecchi, É., Trouplin, V., Коrogod, S. М., & Brocard, F. (2021) · Nature Communications · doi:10.1038/s41467-021-27113-x · Cited by 28
Molecular Mechanism of Pancreatic β-Cell Failure in Type 2 Diabetes Mellitus
Kaneto, H., Kimura, T., Shimoda, M., Obata, A., Sanada, J., Fushimi, Y., Matsuoka, T., & Kaku, K. (2022) · Biomedicines · doi:10.3390/biomedicines10040818 · Cited by 28
“Third, a physiologically low concentration of GLP-1 activates protein kinase C (PKC) and enhances insulin secretion [102].”
BackgroundSelf-citationKhan, D., Vasu, S., Moffett, R. C., Irwin, N., & Flatt, P. R. (2017) · Peptides · doi:10.1016/j.peptides.2017.07.011 · Cited by 30
“Unlike the recognised insulin secretory actions of GLP-1 [35], GLP-2 did not increase insulin levels in mice, isolated islets or cultured rodent and human 1.”
Feng, J., Zong, P., Yan, J., Yue, Z., Li, X., Smith, C., Ai, X., & Yue, L. (2021) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-021-02525-2 · Cited by 26
TRP Channels as Molecular Targets to Relieve Endocrine-Related Diseases
Liu, Y., Lyu, Y., & Wang, H. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.895814 · Cited by 27
“In addition to being activated by [Ca2+]i, TRPM4/5 can also be activated by PKC, leading to membrane depolarization and increasing insulin secretion (Uchida and Tominaga, 2011; Shigeto et al., 2015; Uchida et al., 2017).”
BackgroundGrespan, E., Toni Giorgino, A., Natali, A., Ferrannini, E., & Mari, A. (2020) · Metabolism · doi:10.1016/j.metabol.2020.154415 · Cited by 25
Molecular regulation of insulin granule biogenesis and exocytosis
Röder, P. V., Wong, X. M., Hong, W., & Han, W. (2016) · Biochemical Journal · doi:10.1042/bcj20160291 · Cited by 25
The GLP-1R as a model for understanding and exploiting biased agonism in next-generation medicines
Douros, J. D., Mokrosiński, J., & Finan, B. (2024) · Journal of Endocrinology · doi:10.1530/joe-23-0226 · Cited by 24
Smits, M. M., & Holst, J. J. (2023) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.3699 · Cited by 22
“107 The clinical relevance of these findings is currently unknown.”
BackgroundYip, L., Fuhlbrigge, R., Alkhataybeh, R., & Fathman, C. G. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.609271 · Cited by 21
“TRPM5 has also been shown to mediate insulin secretion by L-arginine and to potentiate glucose-induced insulin secretion by glucagon-like peptide 1 (88, 89).”
BackgroundCui, Y., Wu, H., Li, Q., JianWen, L., Gao, P., Sun, F., Zhang, H., Lu, Z., Wei, X., He, C., et al. (2019) · Hypertension · doi:10.1161/hypertensionaha.119.13358 · Cited by 22
“TRPM5 channel is also regulated by PKC in a Ca-independent manner.(17) In this study, both the expression and activity levels of TRPM5 or PKCα were dose-dependently inhibited by NaCl in tongue epithelium.”
BackgroundZaborska, K. E., Jordan, K. L., Thorson, A. S., Dadi, P. K., Schaub, C. M., Nakhe, A. Y., Dickerson, M. T., Lynch, J. C., Weiss, A. J., Dobson, J. R., et al. (2022) · Diabetes Obesity and Metabolism · doi:10.1111/dom.14747 · Cited by 21
“12,14-17,22 Moreover, GLP-1 stimulates the activity of voltage-dependent Ca2+ channels by promoting protein kinase A (PKA)-mediated channel phosphorylation.18,21 Further- more, GLP-1R-mediated signalling has been demonstrated to depolarize membrane potential (Vm) by activating monovalent cation permeable transient rec…”
BackgroundProtein kinase C isoforms in the normal pancreas and in pancreatic disease
Martinez, A. K. F., & Störz, P. (2017) · Cellular Signalling · doi:10.1016/j.cellsig.2017.08.005 · Cited by 20
Farnsworth, N. L., Walter, R., Piscopio, R. A., Schleicher, W. E., & Benninger, R. K. P. (2018) · The Journal of Physiology · doi:10.1113/jp276106 · Cited by 25
The LIM homeodomain protein ISL1 mediates the function of TCF7L2 in pancreatic beta cells
Shao, W., Szeto, V., Song, Z., Tian, L., Feng, Z., Nostro, M. C., & Jin, T. (2018) · Journal of Molecular Endocrinology · doi:10.1530/jme-17-0181 · Cited by 20
Rashid, C. S., Lien, Y., Bansal, A., Santos, L. J. J., Li, C., Won, K., & Simmons, R. A. (2018) · Endocrinology · doi:10.1210/en.2017-00888 · Cited by 20
Babateen, O., Korol, S. V., Jin, Z., Bhandage, A. K., Ahemaiti, A., & Birnir, B. (2017) · BMC Pharmacology and Toxicology · doi:10.1186/s40360-017-0191-0 · Cited by 19
An optimized protocol for purification of functional islets of Langerhans
Saliba, Y., Bakhos, J., Itani, T. M., & Farès, N. (2016) · Laboratory Investigation · doi:10.1038/labinvest.2016.123 · Cited by 18
Store-operated Ca2+ entry: a key component of the insulin secretion machinery
Sabourin, J., & Allagnat, F. (2016) · Journal of Molecular Endocrinology · doi:10.1530/jme-16-0106 · Cited by 18
Khajavi, N., Finan, B., Kluth, O., Müller, T. D., Mergler, S., Schulz, A., Kleinau, G., Scheerer, P., Schürmann, A., Gudermann, T. W., et al. (2018) · Cellular Signalling · doi:10.1016/j.cellsig.2018.07.006 · Cited by 16
Liraglutide Promotes Osteoblastic Differentiation in MC3T3-E1 Cells by ERK5 Pathway
Sun, Y., Liang, Y., Li, Z., & Xia, N. (2020) · International Journal of Endocrinology · doi:10.1155/2020/8821077 · Cited by 17
“Following activation by its ligand, the levels of cyclic adenosine phosphate and calcium ions in the cells of the pancreas are increased, triggering glucose-dependent insulin secretion [6].”
BackgroundInfluentialcAMP-independent effects of GLP-1 on β cells
Kolic, J., & MacDonald, P. E. (2015) · Journal of Clinical Investigation · doi:10.1172/jci85004 · Cited by 18
“The fact that Shigeto et al. (15) observed little or no cAMP and PKA activation directly in response to picomolar amounts of GLP-1 is somewhat perplexing.”
BackgroundMethodInfluentialKhajavi, N., Biebermann, H., Tschöp, M. H., & DiMarchi, R. D. (2017) · Endocrine development · doi:10.1159/000475737 · Cited by 18
Mitochondrial Physiology of Cellular Redox Regulations
Ježek, P., Dlasková, A., Engstová, H., Špačková, J., Tauber, J. A., Průchová, P., Klöppel, E., Mozheitová, O., & Jabůrek, M. (2024) · Physiological Research · doi:10.33549/physiolres.935269 · Cited by 18
“The reaction product DAG stimulates protein kinase-C (PKC) iso-enzymes, some of which phosphorylate TRPM4 and TRPM5 [214], which opens these channels, enabling them to activate Ca V channels, similarly to the TRPM2 action upon GSIS.”
BackgroundRoles of TRP and PIEZO receptors in autoimmune diseases
Yang, B., Ma, D., Zhu, X., Wu, Z., An, Q., Zhao, J., Gao, X., & Zhang, L. (2024) · Expert Reviews in Molecular Medicine · doi:10.1017/erm.2023.23 · Cited by 16
“Furthermore, TPPO blockade of TRPM5 inhibits GLP-1-enhanced glucose-induced insulin release (Refs 24, 25, 26).”
Jabůrek, M., Klöppel, E., Průchová, P., Mozheitová, O., Tauber, J. A., Engstová, H., & Ježek, P. (2024) · Redox Biology · doi:10.1016/j.redox.2024.103283 · Cited by 16
“In any case, the facilitation of K ATP -closing and TRPM/NSCC activation (both required for Ca L opening [39 – 45]), which is ensured by pathways downstream of GPR40, requires further investigation.”
InfluentialAssay for Detecting Gαi-Mediated Decreases in cAMP in Living Cells
Tewson, P. H., Martinka, S., Shaner, N. C., Berlot, C. H., Quinn, A. M., & Hughes, T. E. (2018) · SLAS DISCOVERY · doi:10.1177/2472555218786238 · Cited by 16
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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