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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http://hdl.handle.net/10138/234279

Lähdeviite

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

Julkaisun nimi: Lactate-Induced Glucose Output Is Unchanged by Metformin at a Therapeutic Concentration - A Mass Spectrometry Imaging Study of the Perfused Rat Liver
Tekijä: Calza, Giulio; Nyberg, Elisabeth; Mäkinen, Matias; Soliymani, Rabah; Cascone, Annunziata; Lindholm, Dan; Barborini, Emanuele; Baumann, Marc; Lalowski, Maciej; Eriksson, Ove
Tekijän organisaatio: Medicum
Helsinki Institute of Life Science HiLIFE
Faculty of Medicine
University of Helsinki
Protein Chemistry
Department of Biochemistry and Developmental Biology
Ove Eriksson-Rosenberg / Principal Investigator
Marc Baumann / Principal Investigator
Päiväys: 2018-02-22
Kieli: eng
Sivumäärä: 12
Kuuluu julkaisusarjaan: Frontiers in Pharmacology
ISSN: 1663-9812
DOI-tunniste: https://doi.org/10.3389/fphar.2018.00141
URI: http://hdl.handle.net/10138/234279
Tiivistelmä: 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).
Avainsanat: metformin
diabetes
mass spectrometry imaging
liver
gluconeogenesis
lactate
DIABETES-MELLITUS
RESPIRATORY-CHAIN
CANCER
MECHANISM
NIDDM
RISK
METABOLISM
BIGUANIDES
GLUCONEOGENESIS
INHIBITION
317 Pharmacy
3121 General medicine, internal medicine and other clinical medicine
Vertaisarvioitu: Kyllä
Tekijänoikeustiedot: cc_by
Pääsyrajoitteet: openAccess
Rinnakkaistallennettu versio: publishedVersion


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