Metformin in the management of diabetes during pregnancy and lactation

Abstract

This review explores the current place of metformin in the management of gestational diabetes (GDM) and type 2 diabetes during pregnancy and lactation. The rationale and basic pharmacology of metformin usage in pregnancy is discussed along with the evidence from observational and randomized controlled trials in women with GDM or overt diabetes. There seems to be adequate evidence of efficacy and short-term safety of metformin in relation to maternal and neonatal outcomes in GDM, with possible benefits related to lower maternal weight gain and lower risk of neonatal hypoglycemia and macrosomia. Additionally, metformin offers the advantages of oral administration, convenience, less cost and greater acceptability. Metformin may, therefore, be considered in milder forms of GDM where glycemic goals are not attained by lifestyle modification. However, failure rate is likely to be higher in those with an earlier diagnosis of GDM, higher blood glucose, higher body mass index (BMI) or previous history of GDM, and insulin remains the cornerstone of pharmacological treatment in such cases. The use of metformin in type 2 diabetes has been assessed in observational and small randomized trials. Metformin monotherapy in women with overt diabetes is highly unlikely to achieve glycemic targets. Hence, the use should be restricted as adjunct to insulin and may be considered in women with high insulin dose requirements or rapid weight gain. There is clearly a need for more clinical trials to assess the effect of combined insulin plus metformin therapy in pregnancy with type 2 diabetes. Additionally, there is a paucity of data on long-term effects in offspring exposed to metformin in utero. It is imperative to further explore its impact on offspring as metformin has significant transplacental transfer and has the potential to impact the programming of the epigenome. Therefore, caution must be exercised when prescribing metformin in pregnant women. More research is clearly needed before metformin can be considered as standard of care in the management of diabetes during pregnancy.

Keywords: diabetes; epigenetic programming; gestational diabetes; metformin; oral antidiabetic agents; pregnancy; type 2 diabetes.

Figure 1. Mechanism of action of metformin

Metformin is transported across the cell membrane and mitochondrial membrane by organic cation transporters (OCT). Metformin inhibits the complex I of the electron transport chain in the mitochondria, leading to suppression of ATP production. The resultant increase in AMP:ATP ratio and ADP: ATP ratio causes activation of AMP-activated kinase (AMPK), which acts as the cellular energy sensor. AMPK activation leads to a switch in cell metabolism toward catabolic pathways generating energy and suppression energy consuming processes such as gluconeogenesis. Increase in AMP:ATP ratio inhibits fructose-1,6-bisphosphatase, a key enzyme involved in gluconeogenesis. Increased intracellular AMP inhibits adenylate cyclase, with decrease in cAMP production and reduced expression of gluconeogenic enzymes. AMPK activation further results in phosphorylation of acetyl-coA carboxylase and this leads to increased fatty acid oxidation and decreased lipogenesis. Additionally, AMPK activation inhibits mTOR and downstream signaling pathways with decrease in protein synthesis. Abbreviations: ADP, adenosine diphosphate; AMP, adenosine monophosphate; ATP, adenosine triphosphate; cAMP, cyclic AMP; ETC, electron transport chain; FBPase, fructose-1,6-bisphosphatase; mTOR, mammalian target of rapamycin; NADH, nicotinamide adenine dinucleotide; OCT, organic cation transporter; PKA, protein kinase A; ROS, reactive oxygen species.

Figure 2. Mechanisms by which metformin may impact epigenetic programming

Metformin impairs glycolysis and tricarboxylic acid (TCA) cycle, resulting in reduced accumulation of glycolytic and TCA cycle intermediates, including succinate, fumarate, malate, citrate and α-ketoglutarate. Metformin can lead to epigenetic modifications through decrease in histone acetylation, histone phosphorylation and histone methylation. Metformin impairs one-carbon metabolism and has antifolate effect. It can lead to decreased availability of methyl (CH3) groups through sequential conversion of methionine to SAM, SAH and homocysteine. Additionally, metformin has been associated with vitamin B₁₂ deficiency and reduce the regeneration of methionine. Metformin also inhibits mTOR and phosphorylation of its downstream targets and suppression of global protein synthesis. Abbreviations: α-KG, α ketoglutarate; AMP, adenosine monophosphate; AMPK, AMP-activated kinase; ATP, adenosine triphosphate; DHF, dihydrofolate; HAT, histone acetylase; HDMT, histone demethyltransferase; mTOR, mammalian target of rapamycin; NAD, nicotinamide adenine dinucleotide; SAH, S-adenosyl homocysteine; SAM, S-adenosyl methionine; SIRT1, sirtuin 1; THF, tetrahydrofolate.