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.
authors.forename: Makoto
authors.initials: M
authors.lastname: Shigeto
authors.forename: Reshma
authors.initials: R
authors.lastname: Ramracheya
authors.forename: Andrei I
authors.initials: AI
authors.lastname: Tarasov
authors.forename: Chae Young
authors.initials: CY
authors.lastname: Cha
authors.forename: Margarita V
authors.initials: MV
authors.lastname: Chibalina
authors.forename: Benoit
authors.initials: B
authors.lastname: Hastoy
authors.forename: Koenraad
authors.initials: K
authors.lastname: Philippaert
authors.forename: Thomas
authors.initials: T
authors.lastname: Reinbothe
authors.forename: Nils
authors.initials: N
authors.lastname: Rorsman
authors.forename: Albert
authors.initials: A
authors.lastname: Salehi
authors.forename: William R
authors.initials: WR
authors.lastname: Sones
authors.forename: Elisa
authors.initials: E
authors.lastname: Vergari
authors.forename: Cathryn
authors.initials: C
authors.lastname: Weston
authors.forename: Julia
authors.initials: J
authors.lastname: Gorelik
authors.forename: Masashi
authors.initials: M
authors.lastname: Katsura
authors.forename: Viacheslav O
authors.initials: VO
authors.lastname: Nikolaev
authors.forename: Rudi
authors.initials: R
authors.lastname: Vennekens
authors.forename: Manuela
authors.initials: M
authors.lastname: Zaccolo
authors.forename: Antony
authors.initials: A
authors.lastname: Galione
authors.forename: Paul R V
authors.initials: PR
authors.lastname: Johnson
authors.forename: Kohei
authors.initials: K
authors.lastname: Kaku
authors.forename: Graham
authors.initials: G
authors.lastname: Ladds
authors.forename: Patrik
authors.initials: P
authors.lastname: Rorsman
mesh_terms: D000818:Animals; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D017136:Ion Transport / Q000187:drug effects / Q000235:genetics; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D007328:Insulin; D050053:TRPM Cation Channels; C437888:TRPM4 protein, human; C476766:TRPM4 protein, mouse; C404409:TRPM5 protein, human; C498617:Trpm5 protein, mouse; D052216:Glucagon-Like Peptide 1; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate