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

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        81975.2_20180710114729_covered_253bed37ca4c1ab43d105aefdf7b5536.pdf (PDF, 1Mb)
        Author
        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
        Attention
        2299/20514
        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.
        Publication date
        2015-12-01
        Published in
        Journal of Clinical Investigation
        Published version
        https://doi.org/10.1172/JCI81975
        Other links
        http://hdl.handle.net/2299/20514
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