Please use this identifier to cite or link to this item: http://hdl.handle.net/1893/16516
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dc.contributor.authorLogie, Lisaen_UK
dc.contributor.authorHarthill, Jeanen_UK
dc.contributor.authorPatel, Kashyapen_UK
dc.contributor.authorBacon, Sandraen_UK
dc.contributor.authorHamilton, David Leeen_UK
dc.contributor.authorMacrae, Katherineen_UK
dc.contributor.authorMcDougall, Gordonen_UK
dc.contributor.authorWang, Huan-Huanen_UK
dc.contributor.authorXue, Linen_UK
dc.contributor.authorJiang, Huaen_UK
dc.contributor.authorSakamoto, Keien_UK
dc.contributor.authorPrescott, Alan Ren_UK
dc.contributor.authorRena, Grahamen_UK
dc.date.accessioned2016-09-10T00:26:02Z-
dc.date.available2016-09-10T00:26:02Zen_UK
dc.date.issued2012-06en_UK
dc.identifier.urihttp://hdl.handle.net/1893/16516-
dc.description.abstractIn recent decades, the antihyperglycemic biguanide metformin has been used extensively in the treatment of type 2 diabetes, despite continuing uncertainty over its direct target. In this article, using two independent approaches, we demonstrate that cellular actions of metformin are disrupted by interference with its metal-binding properties, which have been known for over a century but little studied by biologists. We demonstrate that copper sequestration opposes known actions of metformin not only on AMP-activated protein kinase (AMPK)-dependent signaling, but also on S6 protein phosphorylation. Biguanide/metal interactions are stabilized by extensive π-electron delocalization and by investigating analogs of metformin; we provide evidence that this intrinsic property enables biguanides to regulate AMPK, glucose production, gluconeogenic gene expression, mitochondrial respiration, and mitochondrial copper binding. In contrast, regulation of S6 phosphorylation is prevented only by direct modification of the metal-liganding groups of the biguanide structure, supporting recent data that AMPK and S6 phosphorylation are regulated independently by biguanides. Additional studies with pioglitazone suggest that mitochondrial copper is targeted by both of these clinically important drugs. Together, these results suggest that cellular effects of biguanides depend on their metal-binding properties. This link may illuminate a better understanding of the molecular mechanisms enabling antihyperglycemic drug action.en_UK
dc.language.isoenen_UK
dc.publisherAmerican Diabetes Associationen_UK
dc.relationLogie L, Harthill J, Patel K, Bacon S, Hamilton DL, Macrae K, McDougall G, Wang H, Xue L, Jiang H, Sakamoto K, Prescott AR & Rena G (2012) Cellular Responses to the Metal-Binding Properties of Metformin. Diabetes, 61 (6), pp. 1423-1433. https://doi.org/10.2337/db11-0961en_UK
dc.rightsThe publisher does not allow this work to be made publicly available in this Repository. Please use the Request a Copy feature at the foot of the Repository record to request a copy directly from the author. You can only request a copy if you wish to use this work for your own research or private study.en_UK
dc.rights.urihttp://www.rioxx.net/licenses/under-embargo-all-rights-reserveden_UK
dc.titleCellular Responses to the Metal-Binding Properties of Metforminen_UK
dc.typeJournal Articleen_UK
dc.rights.embargodate2999-12-31en_UK
dc.rights.embargoreason[Cellular Responses to the Metal-Binding Properties of Metformin.pdf] The publisher does not allow this work to be made publicly available in this Repository therefore there is an embargo on the full text of the work.en_UK
dc.identifier.doi10.2337/db11-0961en_UK
dc.citation.jtitleDiabetesen_UK
dc.citation.issn1939-327Xen_UK
dc.citation.issn0012-1797en_UK
dc.citation.volume61en_UK
dc.citation.issue6en_UK
dc.citation.spage1423en_UK
dc.citation.epage1433en_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.contributor.affiliationUniversity of Dundeeen_UK
dc.contributor.affiliationUniversity of Dundeeen_UK
dc.contributor.affiliationUniversity of Dundeeen_UK
dc.contributor.affiliationUniversity of Dundeeen_UK
dc.contributor.affiliationSporten_UK
dc.contributor.affiliationUniversity of Dundeeen_UK
dc.contributor.affiliationThe James Hutton Instituteen_UK
dc.contributor.affiliationChinese Academy of Sciencesen_UK
dc.contributor.affiliationChinese Academy of Sciencesen_UK
dc.contributor.affiliationChinese Academy of Sciencesen_UK
dc.contributor.affiliationUniversity of Dundeeen_UK
dc.contributor.affiliationUniversity of Dundeeen_UK
dc.contributor.affiliationUniversity of Dundeeen_UK
dc.identifier.isiWOS:000304490100019en_UK
dc.identifier.scopusid2-s2.0-84861887451en_UK
dc.identifier.wtid761646en_UK
dc.contributor.orcid0000-0002-5620-4788en_UK
dcterms.dateAccepted2012-06-30en_UK
dc.date.filedepositdate2013-08-23en_UK
rioxxterms.typeJournal Article/Reviewen_UK
rioxxterms.versionVoRen_UK
local.rioxx.authorLogie, Lisa|en_UK
local.rioxx.authorHarthill, Jean|en_UK
local.rioxx.authorPatel, Kashyap|en_UK
local.rioxx.authorBacon, Sandra|en_UK
local.rioxx.authorHamilton, David Lee|0000-0002-5620-4788en_UK
local.rioxx.authorMacrae, Katherine|en_UK
local.rioxx.authorMcDougall, Gordon|en_UK
local.rioxx.authorWang, Huan-Huan|en_UK
local.rioxx.authorXue, Lin|en_UK
local.rioxx.authorJiang, Hua|en_UK
local.rioxx.authorSakamoto, Kei|en_UK
local.rioxx.authorPrescott, Alan R|en_UK
local.rioxx.authorRena, Graham|en_UK
local.rioxx.projectInternal Project|University of Stirling|https://isni.org/isni/0000000122484331en_UK
local.rioxx.freetoreaddate2999-12-31en_UK
local.rioxx.licencehttp://www.rioxx.net/licenses/under-embargo-all-rights-reserved||en_UK
local.rioxx.filenameCellular Responses to the Metal-Binding Properties of Metformin.pdfen_UK
local.rioxx.filecount1en_UK
local.rioxx.source0012-1797en_UK
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