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

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 JohnsonKohei Kaku, Graham Ladds, Patrik Rorsman

Research output: Contribution to journalArticlepeer-review

90 Citations (Scopus)
8 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)4714-28
Number of pages15
JournalJournal of Clinical Investigation
Volume125
Issue number12
Early online date16 Nov 2015
DOIs
Publication statusPublished - 1 Dec 2015

Keywords

  • Animals
  • Glucagon-Like Peptide 1/pharmacology
  • Humans
  • Insulin/genetics
  • Insulin-Secreting Cells/cytology
  • Ion Transport/drug effects
  • Membrane Potentials/drug effects
  • Mice
  • Mice, Knockout
  • Protein Kinase C/genetics
  • TRPM Cation Channels/genetics
  • Tetradecanoylphorbol Acetate/pharmacology

Fingerprint

Dive into the research topics of 'GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation'. Together they form a unique fingerprint.

Cite this