University of Hertfordshire

From the same journal

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

Research output: Contribution to journalArticlepeer-review


  • Makoto Shigeto
  • Reshma Ramracheya
  • Andrei I Tarasov
  • Chae Young Cha
  • Margarita V Chibalina
  • Benoit Hastoy
  • Koenraad Philippaert
  • Thomas Reinbothe
  • Nils Rorsman
  • Albert Salehi
  • William R Sones
  • Elisa Vergari
  • Cathryn Weston
  • Julia Gorelik
  • Masashi Katsura
  • Viacheslav O Nikolaev
  • Rudi Vennekens
  • Manuela Zaccolo
  • Antony Galione
  • Paul R V Johnson
  • And 3 others
  • Kohei Kaku
  • Graham Ladds
  • Patrik Rorsman
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Original languageEnglish
Pages (from-to)4714-28
Number of pages15
JournalJournal of Clinical Investigation
Early online date16 Nov 2015
Publication statusPublished - 1 Dec 2015


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.

ID: 15267065