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      Interaction between Metformin, Folate and Vitamin B 12 and the Potential Impact on Fetal Growth and Long-Term Metabolic Health in Diabetic Pregnancies

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          Abstract

          Metformin is the first-line treatment for many people with type 2 diabetes mellitus (T2DM) and gestational diabetes mellitus (GDM) to maintain glycaemic control. Recent evidence suggests metformin can cross the placenta during pregnancy, thereby exposing the fetus to high concentrations of metformin and potentially restricting placental and fetal growth. Offspring exposed to metformin during gestation are at increased risk of being born small for gestational age (SGA) and show signs of ‘catch up’ growth and obesity during childhood which increases their risk of future cardiometabolic diseases. The mechanisms by which metformin impacts on the fetal growth and long-term health of the offspring remain to be established. Metformin is associated with maternal vitamin B 12 deficiency and antifolate like activity. Vitamin B 12 and folate balance is vital for one carbon metabolism, which is essential for DNA methylation and purine/pyrimidine synthesis of nucleic acids. Folate:vitamin B 12 imbalance induced by metformin may lead to genomic instability and aberrant gene expression, thus promoting fetal programming. Mitochondrial aerobic respiration may also be affected, thereby inhibiting placental and fetal growth, and suppressing mammalian target of rapamycin (mTOR) activity for cellular nutrient transport. Vitamin supplementation, before or during metformin treatment in pregnancy, could be a promising strategy to improve maternal vitamin B 12 and folate levels and reduce the incidence of SGA births and childhood obesity. Heterogeneous diagnostic and screening criteria for GDM and the transient nature of nutrient biomarkers have led to inconsistencies in clinical study designs to investigate the effects of metformin on folate:vitamin B 12 balance and child development. As rates of diabetes in pregnancy continue to escalate, more women are likely to be prescribed metformin; thus, it is of paramount importance to improve our understanding of metformin’s transgenerational effects to develop prophylactic strategies for the prevention of adverse fetal outcomes.

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          One-Carbon Metabolism in Health and Disease.

          One-carbon (1C) metabolism, mediated by the folate cofactor, supports multiple physiological processes. These include biosynthesis (purines and thymidine), amino acid homeostasis (glycine, serine, and methionine), epigenetic maintenance, and redox defense. Both within eukaryotic cells and across organs, 1C metabolic reactions are compartmentalized. Here we review the fundamentals of mammalian 1C metabolism, including the pathways active in different compartments, cell types, and biological states. Emphasis is given to recent discoveries enabled by modern genetics, analytical chemistry, and isotope tracing. An emerging theme is the biological importance of mitochondrial 1C reactions, both for producing 1C units that are exported to the cytosol and for making additional products, including glycine and NADPH. Increased clarity regarding differential folate pathway usage in cancer, stem cells, development, and adult physiology is reviewed and highlights new opportunities for selective therapeutic intervention.
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            N6-methyladenosine marks primary microRNAs for processing.

            The first step in the biogenesis of microRNAs is the processing of primary microRNAs (pri-miRNAs) by the microprocessor complex, composed of the RNA-binding protein DGCR8 and the type III RNase DROSHA. This initial event requires recognition of the junction between the stem and the flanking single-stranded RNA of the pri-miRNA hairpin by DGCR8 followed by recruitment of DROSHA, which cleaves the RNA duplex to yield the pre-miRNA product. While the mechanisms underlying pri-miRNA processing have been determined, the mechanism by which DGCR8 recognizes and binds pri-miRNAs, as opposed to other secondary structures present in transcripts, is not understood. Here we find in mammalian cells that methyltransferase-like 3 (METTL3) methylates pri-miRNAs, marking them for recognition and processing by DGCR8. Consistent with this, METTL3 depletion reduced the binding of DGCR8 to pri-miRNAs and resulted in the global reduction of mature miRNAs and concomitant accumulation of unprocessed pri-miRNAs. In vitro processing reactions confirmed the sufficiency of the N(6)-methyladenosine (m(6)A) mark in promoting pri-miRNA processing. Finally, gain-of-function experiments revealed that METTL3 is sufficient to enhance miRNA maturation in a global and non-cell-type-specific manner. Our findings reveal that the m(6)A mark acts as a key post-transcriptional modification that promotes the initiation of miRNA biogenesis.
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              Prevalence of Gestational Diabetes and Risk of Progression to Type 2 Diabetes: a Global Perspective.

              Despite the increasing epidemic of diabetes mellitus affecting populations at different life stages, the global burden of gestational diabetes mellitus (GDM) is not well assessed. Systematically synthesized data on global prevalence estimates of GDM are lacking, particularly among developing countries. The hyperglycemic intrauterine environment as exemplified in pregnancies complicated by GDM might not only reflect but also fuel the epidemic of type 2 diabetes mellitus (T2DM). We comprehensively reviewed available data in the past decade in an attempt to estimate the contemporary global prevalence of GDM by country and region. We reviewed the risk of progression from GDM to T2DM as well. Synthesized data demonstrate wide variations in both prevalence estimates of GDM and the risk of progression from GDM to T2DM. Direct comparisons of GDM burden across countries or regions are challenging given the great heterogeneity in screening approaches, diagnostic criteria, and underlying population characteristics. In this regard, collaborative efforts to estimate global GDM prevalence would be a large but important leap forward. Such efforts may have substantial public health implications in terms of informing health policy makers and healthcare providers for disease burden and for developing more targeted and effective diabetes prevention and management strategies globally.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                28 May 2021
                June 2021
                : 22
                : 11
                : 5759
                Affiliations
                [1 ]Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9JT, UK; ummdo@ 123456leeds.ac.uk
                [2 ]Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, University of Manchester, Manchester M13 9WL, UK; bernadette.baker@ 123456manchester.ac.uk
                [3 ]St Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK
                [4 ]Clinical and Population Sciences, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9JT, UK; E.M.Scott@ 123456leeds.ac.uk
                Author notes
                Author information
                https://orcid.org/0000-0003-0048-0465
                https://orcid.org/0000-0002-3745-1337
                Article
                ijms-22-05759
                10.3390/ijms22115759
                8198407
                34071182
                02e263a0-619b-49f2-a335-83dd32f17f5f
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

                History
                : 01 May 2021
                : 25 May 2021
                Categories
                Review

                Molecular biology
                metformin,diabetes,placenta,folate,vitamin b12,one carbon metabolism,fetal growth,lga,sga,fetal programming

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