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Front. Pharmacol. | doi: 10.3389/fphar.2018.00141

Lactate-induced glucose output is unchanged by metformin at a therapeutic concentration - a mass spectrometry imaging study of the perfused rat liver

 Giulio Calza1, Elisabeth Nyberg1, 2, Matias Mäkinen2,  Rabah Soliymani1,  Annunziata Cascone2,  Dan Lindholm2, 3, Emanuele Barborini4, Marc Baumann1,  Maciej M. Lalowski1 and  Ove Eriksson2*
  • 1Meilahti Clinical Proteomics Core facility, HiLIFE, University of Helsinki, Finland
  • 2Biochemistry and Developmental Biology, University of Helsinki, Finland
  • 3Minerva Foundation Institute for Medical Research, Finland
  • 4Tethis S.p.A, Italy

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 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 m/z 130.16 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 Km 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 µM, metformin did not induce any significant suppression of the basal or lactate-induced glucose release from the liver. These results show that MALDI-MSI 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 inhibiting mitochondrial glycerol 3-phosphate dehydrogenase (EC 1.1.5.3).

Keywords: Metformin, Mass spectrometry imaging, Liver, Gluconeogenesis, Diabetes Mellitus, Type 2

Received: 04 Dec 2017; Accepted: 08 Feb 2018.

Edited by:

Raffaele Capasso, University of Naples Federico II, Italy

Reviewed by:

Guoxun Chen, University of Tennessee, Knoxville, United States
Piotr Widlak, Maria Sklodowska Curie Memorial Institute, Gliwice Branch, Poland  

Copyright: © 2018 Calza, Nyberg, Mäkinen, Soliymani, Cascone, Lindholm, Barborini, Baumann, Lalowski and Eriksson. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Ove Eriksson, University of Helsinki, Biochemistry and Developmental Biology, Biomedicum Helsinki 1, Haartmaninkatu 8, POBox 63, Helsinki, FIN-00290, Finland, ove.eriksson@helsinki.fi