Please use this identifier to cite or link to this item: http://hdl.handle.net/1893/25176
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dc.contributor.authorHaythorne, Elizabethen_UK
dc.contributor.authorHamilton, David Leeen_UK
dc.contributor.authorFindlay, John Aen_UK
dc.contributor.authorBeall, Craigen_UK
dc.contributor.authorMcCrimmon, Rory Jen_UK
dc.contributor.authorAshford, Michael L Jen_UK
dc.date.accessioned2017-03-29T22:37:21Z-
dc.date.available2017-03-29T22:37:21Z-
dc.date.issued2016-12en_UK
dc.identifier.urihttp://hdl.handle.net/1893/25176-
dc.description.abstractIndividuals with Type 1 diabetes(T1D) are often exposed to recurrent episodes of hypoglycaemia. This reduces hormonal and behavioural responses that normally counteract low glucose in order to maintain glucose homeostasis, with altered responsiveness of glucose sensing hypothalamicneurons implicated. Although the molecular mechanisms are unknown, pharmacological studies implicate hypothalamic ATP-sensitive potassium channel (KATP) activity, with KATP openers (KCOs) amplifying, through cell hyperpolarization, the response to hypoglycaemia. Although initial findings, using acute hypothalamic KCO delivery, in rats were promising, chronic exposure to the KCO NN414 worsened the responses to subsequent hypoglycaemic challenge. To investigate this further we used GT1-7cells to explore how NN414 affected glucose-sensing behaviour, the metabolic response of cells to hypoglycaemia and KATP activity. GT1-7 cells exposed to 3 or 24h NN414 exhibited an attenuated hyperpolarization to subsequent hypoglycaemic challenge or NN414, which correlated with diminished KATP activity. The reduced sensitivity to hypoglycaemia was apparent 24 h after NN414 removal, even though intrinsic KATP activity recovered. The NN414-modified glucose responsiveness was not associated with adaptations in glucose uptake, metabolism or oxidation. KATP inactivation by NN414 was prevented by the concurrent presence of tolbutamide, which maintains KATP closure. Single channel recordings indicate that NN414 alters KATP intrinsic gating inducing a stable closed or inactivated state. These data indicate that exposure of hypothalamic glucose sensing cells to chronic NN414 drives a sustained conformational change to KATP, probably by binding to SUR1, that results in loss of channel sensitivity to intrinsic metabolic factors such as MgADP and small molecule agonists.en_UK
dc.language.isoenen_UK
dc.publisherElsevieren_UK
dc.relationHaythorne E, Hamilton DL, Findlay JA, Beall C, McCrimmon RJ & Ashford MLJ (2016) Chronic exposure to KATP channel openers results in attenuated glucose sensing in hypothalamic GT1-7 neurons. Neuropharmacology, 111, pp. 212-222. https://doi.org/10.1016/j.neuropharm.2016.09.008en_UK
dc.rights© 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).en_UK
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_UK
dc.subjectNN414en_UK
dc.subjectDiazoxideen_UK
dc.subjectKATPen_UK
dc.subjectGlucose sensingen_UK
dc.subjectHypoglycemiaen_UK
dc.subjectType 1 diabetesen_UK
dc.titleChronic exposure to KATP channel openers results in attenuated glucose sensing in hypothalamic GT1-7 neuronsen_UK
dc.typeJournal Articleen_UK
dc.identifier.doi10.1016/j.neuropharm.2016.09.008en_UK
dc.identifier.pmid27618741en_UK
dc.citation.jtitleNeuropharmacologyen_UK
dc.citation.issn0028-3908en_UK
dc.citation.volume111en_UK
dc.citation.spage212en_UK
dc.citation.epage222en_UK
dc.citation.publicationstatusPublisheden_UK
dc.citation.peerreviewedRefereeden_UK
dc.type.statusVoR - Version of Recorden_UK
dc.author.emaild.l.hamilton@stir.ac.uken_UK
dc.citation.date09/09/2016en_UK
dc.contributor.affiliationUniversity of Dundeeen_UK
dc.contributor.affiliationSporten_UK
dc.contributor.affiliationUniversity of Dundeeen_UK
dc.contributor.affiliationUniversity of Dundeeen_UK
dc.contributor.affiliationUniversity of Dundeeen_UK
dc.contributor.affiliationUniversity of Dundeeen_UK
dc.identifier.isiWOS:000387197100017en_UK
dc.identifier.scopusid2-s2.0-84987786807en_UK
dc.identifier.wtid533456en_UK
dc.contributor.orcid0000-0002-5620-4788en_UK
dc.date.accepted2016-09-07en_UK
dcterms.dateAccepted2016-09-07en_UK
dc.date.filedepositdate2017-03-17en_UK
rioxxterms.apcnot requireden_UK
rioxxterms.typeJournal Article/Reviewen_UK
rioxxterms.versionVoRen_UK
local.rioxx.authorHaythorne, Elizabeth|en_UK
local.rioxx.authorHamilton, David Lee|0000-0002-5620-4788en_UK
local.rioxx.authorFindlay, John A|en_UK
local.rioxx.authorBeall, Craig|en_UK
local.rioxx.authorMcCrimmon, Rory J|en_UK
local.rioxx.authorAshford, Michael L J|en_UK
local.rioxx.projectInternal Project|University of Stirling|https://isni.org/isni/0000000122484331en_UK
local.rioxx.freetoreaddate2017-03-17en_UK
local.rioxx.licencehttp://creativecommons.org/licenses/by/4.0/|2017-03-17|en_UK
local.rioxx.filename1-s2.0-S0028390816303823-main.pdfen_UK
local.rioxx.filecount1en_UK
local.rioxx.source0028-3908en_UK
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