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GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation

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GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation. / Shigeto, Makoto; Ramracheya, Reshma; Tarasov, Andrei I; Cha, Chae Young; Chibalina, Margarita V; Hastoy, Benoit; Philippaert, Koenraad; Reinbothe, Thomas; Rorsman, Nils; Salehi, Albert; Sones, William R; Vergari, Elisa; Weston, Cathryn; Gorelik, Julia; Katsura, Masashi; Nikolaev, Viacheslav O; Vennekens, Rudi; Zaccolo, Manuela; Galione, Antony; Johnson, Paul R V; Kaku, Kohei; Ladds, Graham; Rorsman, Patrik.

In: J CLIN INVEST, Vol. 125, No. 12, 12.2015, p. 4714-28.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Shigeto, M, Ramracheya, R, Tarasov, AI, Cha, CY, Chibalina, MV, Hastoy, B, Philippaert, K, Reinbothe, T, Rorsman, N, Salehi, A, Sones, WR, Vergari, E, Weston, C, Gorelik, J, Katsura, M, Nikolaev, VO, Vennekens, R, Zaccolo, M, Galione, A, Johnson, PRV, Kaku, K, Ladds, G & Rorsman, P 2015, 'GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation', J CLIN INVEST, vol. 125, no. 12, pp. 4714-28. https://doi.org/10.1172/JCI81975

APA

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., ... Rorsman, P. (2015). GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation. J CLIN INVEST, 125(12), 4714-28. https://doi.org/10.1172/JCI81975

Vancouver

Shigeto M, Ramracheya R, Tarasov AI, Cha CY, Chibalina MV, Hastoy B et al. GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation. J CLIN INVEST. 2015 Dec;125(12):4714-28. https://doi.org/10.1172/JCI81975

Bibtex

@article{8a7a0aa747ea4490b64ced92350e8896,
title = "GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation",
abstract = "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.",
keywords = "Animals, Glucagon-Like Peptide 1, Humans, Insulin, Insulin-Secreting Cells, Ion Transport, Membrane Potentials, Mice, Mice, Knockout, Protein Kinase C, TRPM Cation Channels, Tetradecanoylphorbol Acetate",
author = "Makoto Shigeto and Reshma Ramracheya and Tarasov, {Andrei I} and Cha, {Chae Young} and Chibalina, {Margarita V} and Benoit Hastoy and Koenraad Philippaert and Thomas Reinbothe and Nils Rorsman and Albert Salehi and Sones, {William R} and Elisa Vergari and Cathryn Weston and Julia Gorelik and Masashi Katsura and Nikolaev, {Viacheslav O} and Rudi Vennekens and Manuela Zaccolo and Antony Galione and Johnson, {Paul R V} and Kohei Kaku and Graham Ladds and Patrik Rorsman",
year = "2015",
month = dec,
doi = "10.1172/JCI81975",
language = "English",
volume = "125",
pages = "4714--28",
journal = "J CLIN INVEST",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "12",

}

RIS

TY - JOUR

T1 - GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation

AU - Shigeto, Makoto

AU - Ramracheya, Reshma

AU - Tarasov, Andrei I

AU - Cha, Chae Young

AU - Chibalina, Margarita V

AU - Hastoy, Benoit

AU - Philippaert, Koenraad

AU - Reinbothe, Thomas

AU - Rorsman, Nils

AU - Salehi, Albert

AU - Sones, William R

AU - Vergari, Elisa

AU - Weston, Cathryn

AU - Gorelik, Julia

AU - Katsura, Masashi

AU - Nikolaev, Viacheslav O

AU - Vennekens, Rudi

AU - Zaccolo, Manuela

AU - Galione, Antony

AU - Johnson, Paul R V

AU - Kaku, Kohei

AU - Ladds, Graham

AU - Rorsman, Patrik

PY - 2015/12

Y1 - 2015/12

N2 - 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.

AB - 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.

KW - Animals

KW - Glucagon-Like Peptide 1

KW - Humans

KW - Insulin

KW - Insulin-Secreting Cells

KW - Ion Transport

KW - Membrane Potentials

KW - Mice

KW - Mice, Knockout

KW - Protein Kinase C

KW - TRPM Cation Channels

KW - Tetradecanoylphorbol Acetate

U2 - 10.1172/JCI81975

DO - 10.1172/JCI81975

M3 - SCORING: Journal article

C2 - 26571400

VL - 125

SP - 4714

EP - 4728

JO - J CLIN INVEST

JF - J CLIN INVEST

SN - 0021-9738

IS - 12

ER -