Lactate-Induced Glucose Output Is Unchanged by Metformin at a Therapeutic Concentration - A Mass Spectrometry Imaging Study of the Perfused Rat Liver

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dc.contributor.author Calza, Giulio
dc.contributor.author Nyberg, Elisabeth
dc.contributor.author Mäkinen, Matias
dc.contributor.author Soliymani, Rabah
dc.contributor.author Cascone, Annunziata
dc.contributor.author Lindholm, Dan
dc.contributor.author Barborini, Emanuele
dc.contributor.author Baumann, Marc
dc.contributor.author Lalowski, Maciej
dc.contributor.author Eriksson, Ove
dc.date.accessioned 2018-04-16T09:18:01Z
dc.date.available 2018-04-16T09:18:01Z
dc.date.issued 2018-02-22
dc.identifier.citation Calza , G , Nyberg , E , Mäkinen , M , Soliymani , R , Cascone , A , Lindholm , D , Barborini , E , Baumann , M , Lalowski , M & Eriksson , O 2018 , ' Lactate-Induced Glucose Output Is Unchanged by Metformin at a Therapeutic Concentration - A Mass Spectrometry Imaging Study of the Perfused Rat Liver ' , Frontiers in Pharmacology , vol. 9 , 141 . https://doi.org/10.3389/fphar.2018.00141
dc.identifier.other PURE: 104344005
dc.identifier.other PURE UUID: ef2457f8-4742-4476-8f9f-69a352c0b827
dc.identifier.other WOS: 000425761800001
dc.identifier.other Scopus: 85042402353
dc.identifier.other ORCID: /0000-0001-5205-7445/work/43736912
dc.identifier.other ORCID: /0000-0002-3683-4096/work/45019353
dc.identifier.uri http://hdl.handle.net/10138/234279
dc.description.abstract Metformin is the first line drug for type 2 diabetes but its molecular mechanisms remain unclear. Here, we have studied the acute effect of a therapeutically relevant intrahepatic concentration of metformin on glucose production from lactate. We selected the perfused rat liver as experimental system since it enables the complete control of drug dosage. We used MALDI (matrix-assisted laser desorption/ionization) mass spectrometry imaging to estimate the concentration of metformin in the livers and we measured the concentration of glucose in the effluent medium under basal conditions and following lactate addition. MALDI mass spectra of thin-sections of freeze-clamped rat liver perfused with metformin showed a peak at 130.16 m/z which was unambiguously assigned to metformin. The mass spectrometric detection limit was at a tissue concentration of about 250 nM, and uptake of metformin from the perfusion medium to the liver occurred with a K-m of 0.44 mM. Metformin was evenly distributed in the liver irrespective of its concentration in the perfusion medium and the duration of a perfusion. At a parenchymal concentration of 30 mu M, metformin did not induce any significant suppression of the basal or lactate-induced glucose release from the liver. These results show that matrix-assisted laser desorption/ionization mass spectrometry imaging can be applied to estimate the tissue concentration and distribution of metformin in a therapeutically relevant micromolar concentration range. Our findings challenge the view that metformin causes an inhibition of glucose release from the liver by an acute inhibition of mitochondrial glycerol 3-phosphate dehydrogenase (EC 1.1.5.3). en
dc.format.extent 12
dc.language.iso eng
dc.relation.ispartof Frontiers in Pharmacology
dc.rights cc_by
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject metformin
dc.subject diabetes
dc.subject mass spectrometry imaging
dc.subject liver
dc.subject gluconeogenesis
dc.subject lactate
dc.subject DIABETES-MELLITUS
dc.subject RESPIRATORY-CHAIN
dc.subject CANCER
dc.subject MECHANISM
dc.subject NIDDM
dc.subject RISK
dc.subject METABOLISM
dc.subject BIGUANIDES
dc.subject GLUCONEOGENESIS
dc.subject INHIBITION
dc.subject 317 Pharmacy
dc.subject 3121 General medicine, internal medicine and other clinical medicine
dc.title Lactate-Induced Glucose Output Is Unchanged by Metformin at a Therapeutic Concentration - A Mass Spectrometry Imaging Study of the Perfused Rat Liver en
dc.type Article
dc.contributor.organization Medicum
dc.contributor.organization Helsinki Institute of Life Science HiLIFE
dc.contributor.organization Faculty of Medicine
dc.contributor.organization University of Helsinki
dc.contributor.organization Protein Chemistry
dc.contributor.organization Department of Biochemistry and Developmental Biology
dc.contributor.organization Ove Eriksson-Rosenberg / Principal Investigator
dc.contributor.organization Marc Baumann / Principal Investigator
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.3389/fphar.2018.00141
dc.relation.issn 1663-9812
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

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