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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.otherPURE: 15267065
dc.identifier.otherPURE UUID: 7bc7886e-2681-4790-a441-9695885b9df7
dc.identifier.otherPubMed: 26571400
dc.identifier.otherPubMedCentral: PMC4665783
dc.identifier.otherScopus: 84948843973
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.language.isoeng
dc.relation.ispartofJournal of Clinical Investigation
dc.rightsOpen
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
dc.relation.schoolSchool of Life and Medical Sciences
dc.description.versiontypeFinal Published version
dcterms.dateAccepted2015-12-01
rioxxterms.versionVoR
rioxxterms.versionofrecordhttps://doi.org/10.1172/JCI81975
rioxxterms.licenseref.uriOther
rioxxterms.typeJournal Article/Review
herts.preservation.rarelyaccessedtrue
herts.rights.accesstypeOpen


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