dc.contributor.author | Shigeto, Makoto | |
dc.contributor.author | Ramracheya, Reshma | |
dc.contributor.author | Tarasov, Andrei I | |
dc.contributor.author | Cha, Chae Young | |
dc.contributor.author | Chibalina, Margarita V | |
dc.contributor.author | Hastoy, Benoit | |
dc.contributor.author | Philippaert, Koenraad | |
dc.contributor.author | Reinbothe, Thomas | |
dc.contributor.author | Rorsman, Nils | |
dc.contributor.author | Salehi, Albert | |
dc.contributor.author | Sones, William R | |
dc.contributor.author | Vergari, Elisa | |
dc.contributor.author | Weston, Cathryn | |
dc.contributor.author | Gorelik, Julia | |
dc.contributor.author | Katsura, Masashi | |
dc.contributor.author | Nikolaev, Viacheslav O | |
dc.contributor.author | Vennekens, Rudi | |
dc.contributor.author | Zaccolo, Manuela | |
dc.contributor.author | Galione, Antony | |
dc.contributor.author | Johnson, Paul R V | |
dc.contributor.author | Kaku, Kohei | |
dc.contributor.author | Ladds, Graham | |
dc.contributor.author | Rorsman, Patrik | |
dc.date.accessioned | 2018-09-05T00:12:38Z | |
dc.date.available | 2018-09-05T00:12:38Z | |
dc.date.issued | 2015-12-01 | |
dc.identifier.citation | Shigeto , M , Ramracheya , R , Tarasov , A I , Cha , C Y , Chibalina , M V , Hastoy , B , Philippaert , K , Reinbothe , T , Rorsman , N , Salehi , A , Sones , W R , Vergari , E , Weston , C , Gorelik , J , Katsura , M , Nikolaev , V O , Vennekens , R , Zaccolo , M , Galione , A , Johnson , P R V , Kaku , K , Ladds , G & Rorsman , P 2015 , ' GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation ' , Journal of Clinical Investigation , vol. 125 , no. 12 , pp. 4714-28 . https://doi.org/10.1172/JCI81975 | |
dc.identifier.issn | 0021-9738 | |
dc.identifier.other | PubMedCentral: PMC4665783 | |
dc.identifier.other | ORCID: /0000-0002-8883-176X/work/62751485 | |
dc.identifier.uri | http://hdl.handle.net/2299/20514 | |
dc.description.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. | en |
dc.format.extent | 15 | |
dc.format.extent | 1636100 | |
dc.language.iso | eng | |
dc.relation.ispartof | Journal of Clinical Investigation | |
dc.subject | Animals | |
dc.subject | Glucagon-Like Peptide 1/pharmacology | |
dc.subject | Humans | |
dc.subject | Insulin/genetics | |
dc.subject | Insulin-Secreting Cells/cytology | |
dc.subject | Ion Transport/drug effects | |
dc.subject | Membrane Potentials/drug effects | |
dc.subject | Mice | |
dc.subject | Mice, Knockout | |
dc.subject | Protein Kinase C/genetics | |
dc.subject | TRPM Cation Channels/genetics | |
dc.subject | Tetradecanoylphorbol Acetate/pharmacology | |
dc.title | GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation | en |
dc.contributor.institution | School of Life and Medical Sciences | |
dc.contributor.institution | Department of Biological and Environmental Sciences | |
dc.contributor.institution | Biosciences Research Group | |
dc.description.status | Peer reviewed | |
rioxxterms.versionofrecord | 10.1172/JCI81975 | |
rioxxterms.type | Journal Article/Review | |
herts.preservation.rarelyaccessed | true | |