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Cited by 56Folate and B Vitamins ResearchGestational Diabetes Research and ManagementMetabolism and Genetic Disorders

High Folate, Perturbed One-Carbon Metabolism and Gestational Diabetes Mellitus

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Williamson, Jessica M., Arthurs, Anya L., Smith, Melanie D., Roberts, Claire T., Jankovic-Karasoulos, Tanja·2022·Nutrients
DOI 10.3390/nu14193930PMC PMC9573299
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Abstract

Folate is a dietary micronutrient essential to one-carbon metabolism. The World Health Organisation recommends folic acid (FA) supplementation pre-conception and in early pregnancy to reduce the risk of fetal neural tube defects (NTDs). Subsequently, many countries (~92) have mandatory FA fortification policies, as well as recommendations for periconceptional FA supplementation. Mandatory fortification initiatives have been largely successful in reducing the incidence of NTDs. However, humans have limited capacity to incorporate FA into the one-carbon metabolic pathway, resulting in the increasingly ubiquitous presence of circulating unmetabolised folic acid (uFA). Excess FA intake has emerged as a risk factor in gestational diabetes mellitus (GDM). Several other one-carbon metabolism components (vitamin B12, homocysteine and choline-derived betaine) are also closely entwined with GDM risk, suggesting a role for one-carbon metabolism in GDM pathogenesis. There is growing evidence from in vitro and animal studies suggesting a role for excess FA in dysregulation of one-carbon metabolism. Specifically, high levels of FA reduce methylenetetrahydrofolate reductase (MTHFR) activity, dysregulate the balance of thymidylate synthase (TS) and methionine synthase (MTR) activity, and elevate homocysteine. High homocysteine is associated with increased oxidative stress and trophoblast apoptosis and reduced human chorionic gonadotrophin (hCG) secretion and pancreatic β-cell function. While the relationship between high FA, perturbed one-carbon metabolism and GDM pathogenesis is not yet fully understood, here we summarise the current state of knowledge. Given rising rates of GDM, now estimated to be 14% globally, and widespread FA food fortification, further research is urgently needed to elucidate the mechanisms which underpin GDM pathogenesis.

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Authors
Williamson, J. M., Arthurs, A. L., Smith, M. D., Roberts, C. T., & Jankovic-Karasoulos, T.
Affiliations
  • Flinders University (AU)
  • Pregnancy Health and Beyond Laboratory, Flinders Health and Medical Research Institute, Flinders University, Adelaide, SA 5042, Australia
Corresponding author
  • Williamson, Jessica M.
  • Roberts, Claire T.
ORCID
Venue
Nutrients
Publisher
MDPI AG
Published
2022-09-22
Volume
14
Issue
19
Pages
3930
ISSN
2072-6643 (ISSN-L)
DOI
10.3390/nu14193930
PMC
PMC9573299
OpenAlex
W4296614189
Cited by
56
References
10
Citations by year
2026: 12 · 2025: 28 · 2024: 10 · 2023: 6
FWCI
1.81
Type
journal article
Language
en
Open access
Licence
Locations
  • Nutrients (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Flinders Health and Medical Research Institute (FHMRI) (GNT1174971, GNT1161079, 2021)
  • National Health and Medical Research Council (NHMRC) (GNT1174971, GNT1161079, 2021)
  • Flinders University (GNT1174971, GNT1161079, 2021)
  • Flinders Foundation Health Seed Grant (GNT1174971, GNT1161079, 2021)
Topics
  • Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
  • Health Sciences › Medicine › Obstetrics and Gynecology › Gestational Diabetes Research and Management
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords
gestational diabetes mellitus, folic acid, one-carbon metabolism, folic acid fortification, homocysteine, methylenetetrahydrofolate reductase, thymidylate synthase, methionine synthase, vitamin B12, oxidative stress, trophoblast apoptosis, human chorionic gonadotropin, beta-cell function, neural tube defects
MeSH terms
Animals, Betaine, Carbon, Choline, Female, Folic Acid, Homocysteine, Humans, Neural Tube Defects, Pregnancy, 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase, Thymidylate Synthase, Vitamin B 12, Diabetes, Gestational, Micronutrients, Methylenetetrahydrofolate Reductase (NADPH2)

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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