Preeclampsia, ADMA, and Metformin
When pregnant women receive metformin for any reason, there is a reduction in the risk of preeclampsia of about 30%. Metformin reduced weight gain in pregnancy by 17% or three and a half pounds. Excessive weight gain is associated with complications including increased risk of fetal growth anomalies, risk of diabetes during pregnancy, cesarean delivery and pre-eclampsia. It is also associated with long-term (later in life) health risks to the mother including post-partum weight retention, obesity, and increased risk of developing type 2 diabetes and cardiovascular disease. Scientific advances can help us understand why metformin has these benefits.
Asymmetric dimethyarginine (ADMA) may be the most fascinating small molecule in all medicine. If a fetus lacks the gene responsible for making ADMA, it survives less than a week after the egg is fertilized. That is because ADMA is essential in regulating genes involved in fetal development. The DNA in every cell is the same and it is present in the single cell that results from conception. The process that regulates that single cell becoming a normal infant is called epigenetics. It determines which genes will be switched on or off and it regulates that process very precisely. Epigenetics regulates the place, duration, and intensity of gene activation.
ADMA is central to the epigenetic process. There are proteins surrounding each gene that keep it tightly wound in an inactive state. Arginine is an amino acid present in these proteins. The left side of the ADMA molecule has two methyl (CH3) groups. ADMA is formed when those methyl groups are added to arginine in those proteins. That switches on the gene. It opens it up. Then when the gene’s work is done, the protein is broken down and free ADMA enters the circulation.
Here is the really strange part. ADMA is elevated in every cardiovascular risk factor, it increases oxidant production, and it seems to be part of the cardiovascular disease process in adults. ADMA is essential to the fetus and deadly in adults. ADMA levels are higher in women who later develop preeclampsia. mTOR is a master genetic switch that coordinates food supply with growth in the fetus. Amino acids in foods switch on mTOR to promote fetal growth. ADMA increases when you drink a milkshake and it also switches on mTOR. Metformin switches off mTOR and blocks ADMA induced mTOR activation. That central fact produces metformin benefit in pregnant women and prevents heart attack in older women. These molecular processes impact every cell and organ in the body. Understanding this science has practical application now.