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

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...

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Autores principales: Calza, Giulio, Nyberg, Elisabeth, Mäkinen, Matias, Soliymani, Rabah, Cascone, Annunziata, Lindholm, Dan, Barborini, Emanuele, Baumann, Marc, Lalowski, Maciej, Eriksson, Ove
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5827415/
https://www.ncbi.nlm.nih.gov/pubmed/29520235
http://dx.doi.org/10.3389/fphar.2018.00141
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author Calza, Giulio
Nyberg, Elisabeth
Mäkinen, Matias
Soliymani, Rabah
Cascone, Annunziata
Lindholm, Dan
Barborini, Emanuele
Baumann, Marc
Lalowski, Maciej
Eriksson, Ove
author_facet Calza, Giulio
Nyberg, Elisabeth
Mäkinen, Matias
Soliymani, Rabah
Cascone, Annunziata
Lindholm, Dan
Barborini, Emanuele
Baumann, Marc
Lalowski, Maciej
Eriksson, Ove
author_sort Calza, Giulio
collection PubMed
description 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 μM, 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).
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spelling pubmed-58274152018-03-08 Lactate-Induced Glucose Output Is Unchanged by Metformin at a Therapeutic Concentration – A Mass Spectrometry Imaging Study of the Perfused Rat Liver Calza, Giulio Nyberg, Elisabeth Mäkinen, Matias Soliymani, Rabah Cascone, Annunziata Lindholm, Dan Barborini, Emanuele Baumann, Marc Lalowski, Maciej Eriksson, Ove Front Pharmacol Pharmacology 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 μM, 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). Frontiers Media S.A. 2018-02-22 /pmc/articles/PMC5827415/ /pubmed/29520235 http://dx.doi.org/10.3389/fphar.2018.00141 Text en Copyright © 2018 Calza, Nyberg, Mäkinen, Soliymani, Cascone, Lindholm, Barborini, Baumann, Lalowski and Eriksson. http://creativecommons.org/licenses/by/4.0/ 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.
spellingShingle Pharmacology
Calza, Giulio
Nyberg, Elisabeth
Mäkinen, Matias
Soliymani, Rabah
Cascone, Annunziata
Lindholm, Dan
Barborini, Emanuele
Baumann, Marc
Lalowski, Maciej
Eriksson, Ove
Lactate-Induced Glucose Output Is Unchanged by Metformin at a Therapeutic Concentration – A Mass Spectrometry Imaging Study of the Perfused Rat Liver
title Lactate-Induced Glucose Output Is Unchanged by Metformin at a Therapeutic Concentration – A Mass Spectrometry Imaging Study of the Perfused Rat Liver
title_full Lactate-Induced Glucose Output Is Unchanged by Metformin at a Therapeutic Concentration – A Mass Spectrometry Imaging Study of the Perfused Rat Liver
title_fullStr Lactate-Induced Glucose Output Is Unchanged by Metformin at a Therapeutic Concentration – A Mass Spectrometry Imaging Study of the Perfused Rat Liver
title_full_unstemmed Lactate-Induced Glucose Output Is Unchanged by Metformin at a Therapeutic Concentration – A Mass Spectrometry Imaging Study of the Perfused Rat Liver
title_short Lactate-Induced Glucose Output Is Unchanged by Metformin at a Therapeutic Concentration – A Mass Spectrometry Imaging Study of the Perfused Rat Liver
title_sort lactate-induced glucose output is unchanged by metformin at a therapeutic concentration – a mass spectrometry imaging study of the perfused rat liver
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5827415/
https://www.ncbi.nlm.nih.gov/pubmed/29520235
http://dx.doi.org/10.3389/fphar.2018.00141
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