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, Jahrgang 125, Nr. 12, 12.2015, S. 4714-28.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -