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dc.contributor.authorShigeto, Makoto
dc.contributor.authorRamracheya, Reshma
dc.contributor.authorTarasov, Andrei I
dc.contributor.authorCha, Chae Young
dc.contributor.authorChibalina, Margarita V
dc.contributor.authorHastoy, Benoit
dc.contributor.authorPhilippaert, Koenraad
dc.contributor.authorReinbothe, Thomas
dc.contributor.authorRorsman, Nils
dc.contributor.authorSalehi, Albert
dc.contributor.authorSones, William R
dc.contributor.authorVergari, Elisa
dc.contributor.authorWeston, Cathryn
dc.contributor.authorGorelik, Julia
dc.contributor.authorKatsura, Masashi
dc.contributor.authorNikolaev, Viacheslav O
dc.contributor.authorVennekens, Rudi
dc.contributor.authorZaccolo, Manuela
dc.contributor.authorGalione, Antony
dc.contributor.authorJohnson, Paul R V
dc.contributor.authorKaku, Kohei
dc.contributor.authorLadds, Graham
dc.contributor.authorRorsman, Patrik
dc.date.accessioned2018-09-05T00:12:38Z
dc.date.available2018-09-05T00:12:38Z
dc.date.issued2015-12-01
dc.identifier.citationShigeto , 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.issn0021-9738
dc.identifier.otherPubMedCentral: PMC4665783
dc.identifier.otherORCID: /0000-0002-8883-176X/work/62751485
dc.identifier.urihttp://hdl.handle.net/2299/20514
dc.description.abstractStrategies 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.extent15
dc.format.extent1636100
dc.language.isoeng
dc.relation.ispartofJournal of Clinical Investigation
dc.subjectAnimals
dc.subjectGlucagon-Like Peptide 1/pharmacology
dc.subjectHumans
dc.subjectInsulin/genetics
dc.subjectInsulin-Secreting Cells/cytology
dc.subjectIon Transport/drug effects
dc.subjectMembrane Potentials/drug effects
dc.subjectMice
dc.subjectMice, Knockout
dc.subjectProtein Kinase C/genetics
dc.subjectTRPM Cation Channels/genetics
dc.subjectTetradecanoylphorbol Acetate/pharmacology
dc.titleGLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activationen
dc.contributor.institutionSchool of Life and Medical Sciences
dc.contributor.institutionDepartment of Biological and Environmental Sciences
dc.contributor.institutionBiosciences Research Group
dc.description.statusPeer reviewed
rioxxterms.versionofrecord10.1172/JCI81975
rioxxterms.typeJournal Article/Review
herts.preservation.rarelyaccessedtrue


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