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The mechanism by which imeglimin inhibits gluconeogenesis in rat liver cells

AIMS: To understand the mechanism by which imeglimin (a new oral hypoglycemic agent whose phase 3 development program in Japan has now been completed) decreases hepatic glucose production. MATERIALS AND METHODS: We compared the effect of imeglimin and metformin on glucose production, ATP/ADP ratio,...

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Autores principales: Vial, Guillaume, Lamarche, Frédéric, Cottet‐Rousselle, Cécile, Hallakou‐Bozec, Sophie, Borel, Anne‐Laure, Fontaine, Eric
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8029524/
https://www.ncbi.nlm.nih.gov/pubmed/33855213
http://dx.doi.org/10.1002/edm2.211
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author Vial, Guillaume
Lamarche, Frédéric
Cottet‐Rousselle, Cécile
Hallakou‐Bozec, Sophie
Borel, Anne‐Laure
Fontaine, Eric
author_facet Vial, Guillaume
Lamarche, Frédéric
Cottet‐Rousselle, Cécile
Hallakou‐Bozec, Sophie
Borel, Anne‐Laure
Fontaine, Eric
author_sort Vial, Guillaume
collection PubMed
description AIMS: To understand the mechanism by which imeglimin (a new oral hypoglycemic agent whose phase 3 development program in Japan has now been completed) decreases hepatic glucose production. MATERIALS AND METHODS: We compared the effect of imeglimin and metformin on glucose production, ATP/ADP ratio, oxygen consumption rate, mitochondrial redox potential and membrane potential in primary rat hepatocytes. RESULTS: We found that both imeglimin and metformin dose‐dependently decreased glucose production and the ATP/ADP ratio. Moreover, they both increased mitochondrial redox potential (assessed by mitochondrial NAD(P)H fluorescence) and decreased membrane potential (assessed by TMRM fluorescence). However, contrary to metformin, which inhibits mitochondrial Complex I, imeglimin did not decrease the oxygen consumption rate in intact cells. By measuring the oxygen consumption of in situ respiratory chain as a function of the concentration of NADH, we observed that imeglimin decreased the affinity of NADH for the respiratory chain but did not affect its Vmax (ie competitive inhibition) whereas metformin decreased both the Vmax and the affinity (ie uncompetitive inhibition). CONCLUSIONS: We conclude that imeglimin induces a kinetic constraint on the respiratory chain that does not affect its maximal activity. This kinetic constraint is offset by a decrease in the mitochondrial membrane potential, which induces a thermodynamic constraint on the ATPase responsible for a decrease in the ATP/ADP ratio.
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spelling pubmed-80295242021-04-13 The mechanism by which imeglimin inhibits gluconeogenesis in rat liver cells Vial, Guillaume Lamarche, Frédéric Cottet‐Rousselle, Cécile Hallakou‐Bozec, Sophie Borel, Anne‐Laure Fontaine, Eric Endocrinol Diabetes Metab Original Research Articles AIMS: To understand the mechanism by which imeglimin (a new oral hypoglycemic agent whose phase 3 development program in Japan has now been completed) decreases hepatic glucose production. MATERIALS AND METHODS: We compared the effect of imeglimin and metformin on glucose production, ATP/ADP ratio, oxygen consumption rate, mitochondrial redox potential and membrane potential in primary rat hepatocytes. RESULTS: We found that both imeglimin and metformin dose‐dependently decreased glucose production and the ATP/ADP ratio. Moreover, they both increased mitochondrial redox potential (assessed by mitochondrial NAD(P)H fluorescence) and decreased membrane potential (assessed by TMRM fluorescence). However, contrary to metformin, which inhibits mitochondrial Complex I, imeglimin did not decrease the oxygen consumption rate in intact cells. By measuring the oxygen consumption of in situ respiratory chain as a function of the concentration of NADH, we observed that imeglimin decreased the affinity of NADH for the respiratory chain but did not affect its Vmax (ie competitive inhibition) whereas metformin decreased both the Vmax and the affinity (ie uncompetitive inhibition). CONCLUSIONS: We conclude that imeglimin induces a kinetic constraint on the respiratory chain that does not affect its maximal activity. This kinetic constraint is offset by a decrease in the mitochondrial membrane potential, which induces a thermodynamic constraint on the ATPase responsible for a decrease in the ATP/ADP ratio. John Wiley and Sons Inc. 2021-02-23 /pmc/articles/PMC8029524/ /pubmed/33855213 http://dx.doi.org/10.1002/edm2.211 Text en © 2021 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Research Articles
Vial, Guillaume
Lamarche, Frédéric
Cottet‐Rousselle, Cécile
Hallakou‐Bozec, Sophie
Borel, Anne‐Laure
Fontaine, Eric
The mechanism by which imeglimin inhibits gluconeogenesis in rat liver cells
title The mechanism by which imeglimin inhibits gluconeogenesis in rat liver cells
title_full The mechanism by which imeglimin inhibits gluconeogenesis in rat liver cells
title_fullStr The mechanism by which imeglimin inhibits gluconeogenesis in rat liver cells
title_full_unstemmed The mechanism by which imeglimin inhibits gluconeogenesis in rat liver cells
title_short The mechanism by which imeglimin inhibits gluconeogenesis in rat liver cells
title_sort mechanism by which imeglimin inhibits gluconeogenesis in rat liver cells
topic Original Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8029524/
https://www.ncbi.nlm.nih.gov/pubmed/33855213
http://dx.doi.org/10.1002/edm2.211
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