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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In human β-cells, glucose and sulfonylureas are true initiators of electrical activity.
“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]
The Figure 8 results report spontaneous action potentials in human β-cells at 6 mM glucose. Tolbutamide, a sulfonylurea, increased firing in those cells, but they were already electrically active; the passage does not show it initiating activity in silent human β-cells. (LLM, conf=0.82)
Experimental — accuracy not yet measuredRemoval of extracellular Na+ does not prevent glucose-induced depolarization, which argues that the background inward current cannot be Na+-dependent.
“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]
In the KATP channel-dependent and -independent effects section (Figure 7; page not supplied), the paper says Na+ removal has a weak effect on glucose-induced electrical activity, consistent with depolarization persisting. But it also reports a small change in current with glucose alone and concludes that glucose activates a Na+-permeable conductance to a lesser extent than GLP-1. It therefore does not support the categorical conclusion that the current cannot be Na+-dependent. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTwo-pore channels may not play an important role in glucose-induced electrical activity, at least in mouse β-cells.
“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]
In “GLP-1 increases [Ca²⁺]i in hyperpolarized β cells” (page unavailable), the paper reports that Tpc1/Tpc2 double-knockout islets remained responsive to 20 mM glucose. Figure 10C also shows GLP-1-stimulated electrical activity in knockout β-cells. Neither passage directly establishes that glucose-induced electrical activity is unaffected by loss of the two-pore channels, so the claim is a plausible but more specific inference. (LLM, conf=0.82)
Experimental — accuracy not yet measuredGIIS is little affected in Tpcn1/Tpcn2 double knockout mice.
“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]
In the section ‘GLP-1 increases [Ca²⁺]i in hyperpolarized β cells’ (page not indicated), the paper says Tpc1/Tpc2 double-knockout islets remained responsive to 20 mM glucose. That supports a retained glucose response, but the text does not establish that glucose-induced insulin secretion was ‘little affected’ relative to wild-type islets; its statement of full responsiveness concerns GLP-1. (LLM, conf=0.82)
Experimental — accuracy not yet measuredAmino acids, neurotransmitters and hormones can stimulate electrical activity and insulin release in human β-cells only in the presence of a permissive concentration of glucose.
“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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“Prior observations that Ex-4/GLP-1R signaling may provoke Ca2+ transients in β cells (19, 23, 24, 52) suggested a connection between GLP-1R and calcineurin/NFAT signaling pathways.”
BackgroundAmino Acid Sensing in Metabolic Homeostasis and Health.
Hu, X.-M., & Guo, F. (2020) · Endocrine reviews · doi:10.1210/endrev/bnaa026 · Cited by 123 · see citing works
ATP‐Sensitive Potassium Channels and Their Physiological and Pathophysiological Roles
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Integrating the inputs that shape pancreatic islet hormone release
Noguchi, G. M., & Huising, M. O. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0148-2 · Cited by 130 · see citing works
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“We used GLP-1 at a concentration of 10 nM, in keeping with other islet cell studies (Bode et al. 1999; Tsuboi et al. 2003; de Heer et al. 2008; De Marinis et al. 2010; Shigeto et al. 2015; Traub et al. 2017).”
ResultSelf-citationNew insights into KATP channel gene mutations and neonatal diabetes mellitus
Pipatpolkai, T., Usher, S., Stansfeld, P. J., & Ashcroft, F. M. (2020) · Nature Reviews Endocrinology · doi:10.1038/s41574-020-0351-y · Cited by 122 · see citing works
Revisiting the role of Akkermansia muciniphila as a therapeutic bacterium
Si, J., Kang, H., You, H. J., & Ko, G. (2022) · Gut Microbes · doi:10.1080/19490976.2022.2078619 · Cited by 126 · see citing works
“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.”
BackgroundMarzook, A., Tomas, A., & Jones, B. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.678055 · Cited by 121 · see citing works
“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).”
BackgroundGs/Gq signaling switch in β cells defines incretin effectiveness in diabetes.
Oduori, O. S., Murao, N., Shimomura, K., Takahashi, H., Zhang, Q., Dou, H.-Q., Sakai, S., Minami, K., Chanclón, B., Guida, C., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci140046 · Cited by 85 · see citing works
“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.”
BackgroundSelf-citationCa2+ Regulation of TRP Ion Channels
Hasan, R., & Zhang, X. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19041256 · Cited by 101 · see citing works
“However, the exact Ca2+ binding sites on TRPM5 have not yet been identified.”
BackgroundInfluentialThe therapeutic potential of GLP‐1 receptor biased agonism
Jones, B. J. (2021) · British Journal of Pharmacology · doi:10.1111/bph.15497 · Cited by 99 · see citing works
“In the latter study, both efficacy and potency were higher for Gαs than for Gαq, with some evidence of coupling to Gαi also demonstrated.”
BackgroundInvolvement of thermosensitive TRP channels in energy metabolism
Uchida, K., Dezaki, K., Yoneshiro, T., Watanabe, T., Yamazaki, J., Saito, M., Yada, T., Tominaga, M., & Iwasaki, Y. (2017) · The Journal of Physiological Sciences · doi:10.1007/s12576-017-0552-x · Cited by 95 · see citing works
“GLP-1 stimulates insulin secretion in part by promoting TRPM4 and TRPM5 activation [27].”
BackgroundControl of insulin secretion by GLP-1
Jones, B. J., Bloom, S. R., Buenaventura, T., Tomás, A., & Rutter, G. A. (2018) · Peptides · doi:10.1016/j.peptides.2017.12.013 · Cited by 96 · see citing works
“However, a recent study [59] highlighted a po-”
Glucose-dependent insulinotropic polypeptide (GIP)
Müller, T. D., Adriaenssens, A. E., Ahrén, B., Blüher, M., Birkenfeld, A. L., Campbell, J. E., Coghlan, M. P., D’Alessio, D. D., Deacon, C. F., DelPrato, S., et al. (2025) · Molecular Metabolism · doi:10.1016/j.molmet.2025.102118 · Cited by 99 · see citing works
New Insights into Beta-Cell GLP-1 Receptor and cAMP Signaling
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Glucagon-Like Peptide-1 (GLP-1) in the Integration of Neural and Endocrine Responses to Stress
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The Human Islet: Mini-Organ With Mega-Impact
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Structures of the TRPM5 channel elucidate mechanisms of activation and inhibition
Ruan, Z., Haley, E., Orozco, I. J., Sabat, M. P., Myers, R., Roth, R., Du, J., & Lü, W. (2021) · Nature Structural & Molecular Biology · doi:10.1038/s41594-021-00607-4 · Cited by 68 · see citing works
The Role of cAMP in Beta Cell Stimulus–Secretion and Intercellular Coupling
Stožer, A., Leitgeb, E. P., Pohorec, V., Dolenšek, J., Bombek, L. K., Gosak, M., & Klemen, M. S. (2021) · Cells · doi:10.3390/cells10071658 · Cited by 64 · see citing works
“The effect of cAMP on beta cell Ca2+ signaling is not restricted to the voltage-dependent Ca2+ influx but also involves PKA-dependent and PKA-independent Ca2+ mobilization from internal stores (Figure 2B) [122,127–129].”
BackgroundInfluentialA role of PLC/PKC-dependent pathway in GLP-1-stimulated insulin secretion
Shigeto, M., Cha, C. Y., Rorsman, P., & Kaku, K. (2017) · Journal of Molecular Medicine · doi:10.1007/s00109-017-1508-6 · Cited by 54 · see citing works
“9-39, PKC inhibitors (BIM and calphostin) and L-type Ca channel blocker (isradipine) but persisted in the presence of Rp-8-Br-cAMPS [21].”
InfluentialSelf-citationTRPM5 in the battle against diabetes and obesity
Vennekens, R., Mesuere, M., & Philippaert, K. (2017) · Acta Physiologica · doi:10.1111/apha.12949 · Cited by 52 · see citing works
“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,”
BackgroundInfluentialSelf-citationChen, X.-Y., Chen, L., Yang, W., & Xie, A.-M. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.793004 · Cited by 52 · see citing works
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“In addition, a low concentration of GLP-1 activates PKC without a significant increase of intracellular cAMP, which also leads to the enhancement of insulin secretion [47,48].”
BackgroundSelf-citationPickford, P., Lucey, M., Fang, Z., Bitsi, S., de la Serna, J. B., Broichhagen, J., Hodson, D. J., MINNION, J. S., Rutter, G. A., Bloom, S. R., et al. (2020) · British Journal of Pharmacology · doi:10.1111/bph.15134 · Cited by 49 · see citing works
“Of note, we found that neither ligand was capable of inducing detectable recruitment of Gq, raising questions about the importance of signalling via this G protein in GLP-1R responses (Shigeto et al., 2015), although we cannot exclude cell type-specific effects.”
BackgroundDickerson, M. T., Dadi, P. K., Zaborska, K. E., Nakhe, A. Y., Schaub, C. M., Dobson, J. R., Wright, N. M., Lynch, J. C., Scott, C. F., Robinson, L. D., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-34166-z · Cited by 47 · see citing works
Optical tools for understanding the complexity of β-cell signalling and insulin release
Frank, J. A., Broichhagen, J., Yushchenko, D. A., Trauner, D. H., Schultz, C., & Hodson, D. J. (2018) · Nature Reviews Endocrinology · doi:10.1038/s41574-018-0105-2 · Cited by 46 · see citing works
TRP channels in health and disease at a glance
Yue, L., & Xu, H. (2021) · Journal of Cell Science · doi:10.1242/jcs.258372 · Cited by 49 · see citing works
Henquin, J. (2020) · American Journal of Physiology. Endocrinology and Metabolism · doi:10.1152/ajpendo.00485.2020 · Cited by 39 · see citing works
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“In vitro, human islets stimulated with glucose increase insulin secretion 2 to 3 times upon incretin exposure [39,40].”
Hastoy, B., Godazgar, M., Clark, A., Nylander, V., Spiliotis, I., van de Bunt, M., Chibalina, M., Barrett, A., Burrows, C., Tarasov, A., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-34743-7 · Cited by 42 · see citing works
Self-citationGLP-1R Signaling and Functional Molecules in Incretin Therapy
Wan, W., Qin, Q., Xie, L., Zhang, H., Wu, F., Stevens, R. C., & Liu, Y. (2023) · Molecules · doi:10.3390/molecules28020751 · Cited by 44 · see citing works
“PKC also triggers the closure of the KATP channel and activation of TRPM4/5 [40].”
BackgroundManavi, M. A. (2022) · Neuropeptides · doi:10.1016/j.npep.2022.102250 · Cited by 41 · see citing works
Cabrera, O., FICORILLI, J. V., Shaw, J., Echeverri, F., Schwede, F., Chepurny, O. G., Leech, C. A., & Holz, G. G. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101484 · Cited by 40 · see citing works
Beta‐Cell Ion Channels and Their Role in Regulating Insulin Secretion
Thompson, B. M., & Satin, L. S. (2021) · Comprehensive physiology · doi:10.1002/cphy.c210004 · Cited by 51 · see citing works
GLP1R and GIPR expression and signaling in pancreatic alpha cells, beta cells and delta cells
Shilleh, A. H., Viloria, K., Broichhagen, J., Campbell, J. E., & Hodson, D. J. (2024) · Peptides · doi:10.1016/j.peptides.2024.171179 · Cited by 39 · see citing works
“Similarly, chronic beta cell depolarization via either elevated glucose or K ATP -channel inactivating mutations, leads to a switch from G α s to G α q signaling [71].”
Islam, M. S. (2020) · Cells · doi:10.3390/cells9030685 · Cited by 36 · see citing works
“PKC phosphorylation enhances the sensitivity of the TRPM4 for activation by Ca2+.”
BackgroundInfluentialThermosensation involving thermo-TRPs
Kashio, M. (2020) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2020.111089 · Cited by 38 · see citing works
The Pancreatic β-Cell: The Perfect Redox System
Ježek, P., Holendová, B., Jabůrek, M., Tauber, J., Dlasková, A., & Plecitá-Hlavatá, L. (2021) · Antioxidants · doi:10.3390/antiox10020197 · Cited by 40 · see citing works
“GLP1R-Gαq/11 stimulation occurs, promotion should also be superimposed by the Ca2+induced (meaning by CaV opening) RyR-mediated and or IP3R-mediated Ca2+ release from the ER [279]; plus activating the phosphorylation of TRPM4 and TRPM5 via the DAGPKC pathway [219].”
BackgroundBabinsky, V. N., Hannan, F., Ramracheya, R., Zhang, Q., Nesbit, M., Hugill, A. J., Bentley, L., Hough, T., Joynson, E., Stewart, M. E., et al. (2017) · Endocrinology · doi:10.1210/en.2017-00111 · Cited by 32 · see citing works
“4 with NaOH and glucose as indicated), as reported (25).”
InfluentialSelf-citationIncretin-Based Therapy for Diabetes
Waldrop, G. E., Zhong, J., Peters, M. C., & Rajagopalan, S. (2016) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2015.12.058 · Cited by 36 · see citing works
“Recent evidence at physiologically relevant concentrations of GLP-1 (picomolar range) provides evidence of restoration of β cell competence by these hormones through increased membrane excitability mediated by ion channels (6).”
Recruitment of Epac2A to Insulin Granule Docking Sites Regulates Priming for Exocytosis
Alenkvist, I., Gandasi, N. R., Barg, S., & Tengholm, A. (2017) · Diabetes · doi:10.2337/db17-0050 · Cited by 36 · see citing works
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Protein Kinase C Isozymes and Autophagy during Neurodegenerative Disease Progression
Kaleli, H., Ozer, E., Kaya, V. O., & Kutlu, O. (2020) · Cells · doi:10.3390/cells9030553 · Cited by 30 · see citing works
“Isradipine [199] Benzoxadiazoles Calcium voltage-gated channel subunit alpha1 C Inhibitor GABAergic synapse PKC-α, PKC-β, PKC-γ Increased PKC activity Phase III Completed”
BackgroundGut-liver axis modulation in fructose-fed mice: a role for PPAR-alpha and linagliptin
Silva-Veiga, F. M., Miranda, C. S., Martins, F. F., Daleprane, J. B., Mandarim‐de‐Lacerda, C. A., & Souza‐Mello, V. (2020) · Journal of Endocrinology · doi:10.1530/joe-20-0139 · Cited by 35 · see citing works
Pancreatic β-cell failure, clinical implications, and therapeutic strategies in type 2 diabetes
Cui, D., Feng, X., Lei, S., Zhang, H., Hu, W., Yang, S., Yu, X., & Su, Z. (2024) · Chinese Medical Journal · doi:10.1097/cm9.0000000000003034 · Cited by 36 · see citing works
“…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 · see citing works
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 · see citing works
“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 32 · see citing works
“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 · see citing works
“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 31 · see citing works
Feng, J., Kang, C., Wang, C., Ding, L., Zhu, W., & Hang, S. (2019) · Animals · doi:10.3390/ani9080476 · Cited by 31 · see citing works
“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 · see citing works
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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 · see citing works
“…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 30 · see citing works
Voets, T., Vriens, J., & Vennekens, R. (2019) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2019.07.004 · Cited by 28 · see citing works
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“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 · see citing works
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 27 · see citing works
“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 28 · see citing works
“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 · see citing works
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 · see citing works
“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 · see citing works
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 · see citing works
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 23 · see citing works
Smits, M. M., & Holst, J. J. (2023) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.3699 · Cited by 23 · see citing works
“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 22 · see citing works
“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 · see citing works
“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 · see citing works
“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 21 · see citing works
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 21 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
“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 17 · see citing works
“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 · see citing works
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 16 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
- 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 › Surgery › 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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