Interaction between Metformin, Folate and Vitamin B12 and the Potential Impact on Fetal Growth and Long-Term Metabolic Health in Diabetic Pregnancies

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 B₁₂ deficiency and antifolate like activity. Vitamin B₁₂ and folate balance is vital for one carbon metabolism, which is essential for DNA methylation and purine/pyrimidine synthesis of nucleic acids. Folate:vitamin B₁₂ 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 B₁₂ 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 B₁₂ 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.

Keywords: LGA; SGA; diabetes; fetal growth; fetal programming; folate; metformin; one carbon metabolism; placenta; vitamin B12.

Figure 1

Putative mechanism of action of metformin on cellular metabolism and mitochondrial aerobic respiration to suppress gluconeogenesis. Metformin is an inhibitor of mitochondrial complex I (NADH:ubiquinone oxidoreductase), AMP deaminase, and mitochondrial glycerol 3 phosphate dehydrogenase (G3PDH), which all contribute towards suppression of cellular gluconeogenesis to maintain glycaemic control. ROS, reactive oxygen species; NAD(P)H, nicotinamide adenine dinucleotide phosphate; ATP, adenosine triphosphate; AMP, adenosine monophosphate; cAMP, cyclic AMP; PKA, protein kinase A; mTOR, mammalian target of rapamycin. Black arrows indicate cellular pathway. Orange arrows indicate putative effects of metformin. Figure created using Biorender.com.

Figure 2

One carbon metabolism. Vitamin B₁₂ and folate are co-factors of the methylation and folate cycles which interlink to complete the one carbon metabolism, essential for cell proliferation, differentiation, and growth. DHFR, dihydrofolate reductase; DNMTs, DNA methyltransferase; MAT, methionine adenosyltransferase; MTHFD1, methylenetetrahydrofolate dehydrogenase 1; MTHFR, methylenetetrahydrofolate reductase; MTRR, methyltransferase reductase; SAH, S adenosyl L homocysteine; SAHH, adenosylhomocysteinase; SAM, S-adenosyl methionine; THF, tetrahydrofolate. Figure created using Biorender.com.

Figure 3

Disturbed one carbon metabolism induced by metformin. Metformin reduces vitamin B₁₂, thus impairing the methylation cycle and leading to increased Hcy levels, which are cytotoxic, and hypomethylation of proteins and nucleic acids, which may cause epigenetic changes. The folate cycle is also disturbed by metformin’s antifolate-like activity, thereby reducing pyrimidine and purine synthesis and disrupting cell growth and proliferation. DHFR, dihydrofolate reductase; DNMTs, DNA methyltransferase; MAT, methionine adenosyltransferase; MTHFD1, methylenetetrahydrofolate dehydrogenase 1; MTHFR, methylenetetrahydrofolate reductase; MTRR, methyltransferase reductase; SAH, S adenosyl L homocysteine; SAHH, adenosylhomocysteinase; SAM, S-adenosyl methionine; THF, tetrahydrofolate. Black arrows indicate cellular pathway. Orange arrows indicate putative effects of metformin. Figure created using Biorender.com.

Figure 4

Summary of Proposed Mechanism for metformin effects on placenta and fetus. Figure created using Biorender.com.