ArticleDiabetes2023
Metformin Disrupts Signaling and Metabolism in Fetal Hepatocytes.
Article in Diabetes, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
13 citing papers in PubMed, 17 citations in OpenAlex.
- Can maternal metformin protect the developing fetal brain?American journal of obstetrics and gynecology · 2026Trial
- Placental and cerebral circulation in fetuses of mothers with polycystic ovary syndrome and the effect of Metformin exposure.BMC pregnancy and childbirth · 2025Trial
- Maternal metformin protects developing auditory brainstem function after neonatal hypoxia-ischemia in a neonatal rat model.Clinical and experimental pediatrics · 2026Article
- Metformin as an Innate Immune Modulator: Metabolic and Epigenetic Reprogramming of Innate Immune Cells and Therapeutic Implications.Current issues in molecular biology · 2026Review
- Foetal Metformin Exposure, Childhood Adiposity and Future Cardiovascular Risk: Can We Connect the Dots?TouchREVIEWS in endocrinology · 2025Review
- Long-term effects of metformin on offspring health: A review of current evidence and future directions.Diabetes, obesity & metabolism · 2025Review
- Effect of in utero metformin exposure in gestational diabetes mellitus on infant mesenchymal stem cell metabolism.American journal of physiology. Endocrinology and metabolism · 2025Article
- Metformin administration during pregnancy tends to reduce the risk of gestational diabetes mellitus and improve pregnancy outcomes in previously infertile women with polycystic ovary syndrome who become pregnant.Irish journal of medical science · 2024Article
- Silencing of maternally expressed RNAs in Dlk1-Dio3 domain causes fatal vascular injury in the fetal liver.Cellular and molecular life sciences : CMLS · 2024Article
- Initiation of metformin in early pregnancy results in fetal bioaccumulation, growth restriction, and renal dysmorphology in a primate model.American journal of obstetrics and gynecology · 2024Article
- Metformin use in pregnancy: What about long-term effects in offspring?Acta obstetricia et gynecologica Scandinavica · 2024Article
- Absence of Metformin in Fetal Circulation Following Maternal Administration in Late Gestation Pregnant Sheep.Reproductive sciences (Thousand Oaks, Calif.) · 2024Article
- Metformin in Gestational Diabetes Mellitus: To Use or Not to Use, That Is the Question.Pharmaceuticals (Basel, Switzerland) · 2023Review
Corrections and comments
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Authors and funding
14 authors at 4 institutions in 1 country.
Funding
Abstract
Metformin is used by women during pregnancy to manage diabetes and crosses the placenta, yet its effects on the fetus are unclear. We show that the liver is a site of metformin action in fetal sheep and macaques, given relatively abundant OCT1 transporter expression and hepatic uptake following metformin infusion into fetal sheep. To determine the effects of metformin action, we performed studies in primary hepatocytes from fetal sheep, fetal macaques, and juvenile macaques. Metformin increases AMP-activated protein kinase (AMPK) signaling, decreases mammalian target of rapamycin (mTOR) signaling, and decreases glucose production in fetal and juvenile hepatocytes. Metformin also decreases oxygen consumption in fetal hepatocytes. Unique to fetal hepatocytes, metformin activates stress pathways (e.g., increased PGC1A gene expression, NRF-2 protein abundance, and phosphorylation of eIF2α and CREB proteins) alongside perturbations in hepatokine expression (e.g., increased growth/differentiation factor 15 [GDF15] and fibroblast growth factor 21 [FGF21] expression and decreased insulin-like growth factor 2 [IGF2] expression). Similarly, in liver tissue from sheep fetuses infused with metformin in vivo, AMPK phosphorylation, NRF-2 protein, and PGC1A expression are increased. These results demonstrate disruption of signaling and metabolism, induction of stress, and alterations in hepatokine expression in association with metformin exposure in fetal hepatocytes. ARTICLE HIGHLIGHTS: The major metformin uptake transporter OCT1 is expressed in the fetal liver, and fetal hepatic uptake of metformin is observed in vivo. Metformin activates AMPK, reduces glucose production, and decreases oxygen consumption in fetal hepatocytes, demonstrating similar effects as in juvenile hepatocytes. Unique to fetal hepatocytes, metformin activates metabolic stress pathways and alters the expression of secreted growth factors and hepatokines. Disruption of signaling and metabolism with increased stress pathways and reduced anabolic pathways by metformin in the fetal liver may underlie reduced growth in fetuses exposed to metformin.
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What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.