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Metformin impairs trophoblast metabolism and differentiation in a dose-dependent manner

Metformin is a widely prescribed medication whose mechanism of action is not completely defined and whose role in gestational diabetes management remains controversial. In addition to increasing the risk of fetal growth abnormalities and preeclampsia, gestational diabetes is associated with abnormal...

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Autores principales: Nashif, Sereen K., Mahr, Renee M., Jena, Snehalata, Jo, Seokwon, Nelson, Alisa B., Sadowski, Danielle, Crawford, Peter A., Puchalska, Patrycja, Alejandro, Emilyn U., Gearhart, Micah D., Wernimont, Sarah A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10213689/
https://www.ncbi.nlm.nih.gov/pubmed/37250894
http://dx.doi.org/10.3389/fcell.2023.1167097
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author Nashif, Sereen K.
Mahr, Renee M.
Jena, Snehalata
Jo, Seokwon
Nelson, Alisa B.
Sadowski, Danielle
Crawford, Peter A.
Puchalska, Patrycja
Alejandro, Emilyn U.
Gearhart, Micah D.
Wernimont, Sarah A.
author_facet Nashif, Sereen K.
Mahr, Renee M.
Jena, Snehalata
Jo, Seokwon
Nelson, Alisa B.
Sadowski, Danielle
Crawford, Peter A.
Puchalska, Patrycja
Alejandro, Emilyn U.
Gearhart, Micah D.
Wernimont, Sarah A.
author_sort Nashif, Sereen K.
collection PubMed
description Metformin is a widely prescribed medication whose mechanism of action is not completely defined and whose role in gestational diabetes management remains controversial. In addition to increasing the risk of fetal growth abnormalities and preeclampsia, gestational diabetes is associated with abnormalities in placental development including impairments in trophoblast differentiation. Given that metformin impacts cellular differentiation events in other systems, we assessed metformin’s impact on trophoblast metabolism and differentiation. Using established cell culture models of trophoblast differentiation, oxygen consumption rates and relative metabolite abundance were determined following 200 µM (therapeutic range) and 2000 µM (supra-therapeutic range) metformin treatment using Seahorse and mass-spectrometry approaches. While no differences in oxygen consumption rates or relative metabolite abundance were detected between vehicle and 200 µM metformin-treated cells, 2000 µM metformin impaired oxidative metabolism and increased the abundance of lactate and TCA cycle intermediates, α-ketoglutarate, succinate, and malate. Examining differentiation, treatment with 2000 μM, but not 200 µM metformin, impaired HCG production and expression of multiple trophoblast differentiation markers. Overall, this work suggests that supra-therapeutic concentrations of metformin impair trophoblast metabolism and differentiation whereas metformin concentrations in the therapeutic range do not strongly impact these processes.
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spelling pubmed-102136892023-05-27 Metformin impairs trophoblast metabolism and differentiation in a dose-dependent manner Nashif, Sereen K. Mahr, Renee M. Jena, Snehalata Jo, Seokwon Nelson, Alisa B. Sadowski, Danielle Crawford, Peter A. Puchalska, Patrycja Alejandro, Emilyn U. Gearhart, Micah D. Wernimont, Sarah A. Front Cell Dev Biol Cell and Developmental Biology Metformin is a widely prescribed medication whose mechanism of action is not completely defined and whose role in gestational diabetes management remains controversial. In addition to increasing the risk of fetal growth abnormalities and preeclampsia, gestational diabetes is associated with abnormalities in placental development including impairments in trophoblast differentiation. Given that metformin impacts cellular differentiation events in other systems, we assessed metformin’s impact on trophoblast metabolism and differentiation. Using established cell culture models of trophoblast differentiation, oxygen consumption rates and relative metabolite abundance were determined following 200 µM (therapeutic range) and 2000 µM (supra-therapeutic range) metformin treatment using Seahorse and mass-spectrometry approaches. While no differences in oxygen consumption rates or relative metabolite abundance were detected between vehicle and 200 µM metformin-treated cells, 2000 µM metformin impaired oxidative metabolism and increased the abundance of lactate and TCA cycle intermediates, α-ketoglutarate, succinate, and malate. Examining differentiation, treatment with 2000 μM, but not 200 µM metformin, impaired HCG production and expression of multiple trophoblast differentiation markers. Overall, this work suggests that supra-therapeutic concentrations of metformin impair trophoblast metabolism and differentiation whereas metformin concentrations in the therapeutic range do not strongly impact these processes. Frontiers Media S.A. 2023-05-12 /pmc/articles/PMC10213689/ /pubmed/37250894 http://dx.doi.org/10.3389/fcell.2023.1167097 Text en Copyright © 2023 Nashif, Mahr, Jena, Jo, Nelson, Sadowski, Crawford, Puchalska, Alejandro, Gearhart and Wernimont. https://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(s) 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 Cell and Developmental Biology
Nashif, Sereen K.
Mahr, Renee M.
Jena, Snehalata
Jo, Seokwon
Nelson, Alisa B.
Sadowski, Danielle
Crawford, Peter A.
Puchalska, Patrycja
Alejandro, Emilyn U.
Gearhart, Micah D.
Wernimont, Sarah A.
Metformin impairs trophoblast metabolism and differentiation in a dose-dependent manner
title Metformin impairs trophoblast metabolism and differentiation in a dose-dependent manner
title_full Metformin impairs trophoblast metabolism and differentiation in a dose-dependent manner
title_fullStr Metformin impairs trophoblast metabolism and differentiation in a dose-dependent manner
title_full_unstemmed Metformin impairs trophoblast metabolism and differentiation in a dose-dependent manner
title_short Metformin impairs trophoblast metabolism and differentiation in a dose-dependent manner
title_sort metformin impairs trophoblast metabolism and differentiation in a dose-dependent manner
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10213689/
https://www.ncbi.nlm.nih.gov/pubmed/37250894
http://dx.doi.org/10.3389/fcell.2023.1167097
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