Arginine, ADMA, Metformin: Three of the Most Important Relationships in Biology
The picture shows the structure of the amino acid arginine on the left and the arginine analog ADMA on the right. You can see very easily that the top of the molecules are different, but the bottom is identical. Nitric oxide (NO) is a critical molecule in human biology. It maintains arterial health and it causes the artery to dilate in response to exercise and other stimuli. It is the active ingredient in nitroglycerin that relieves chest pain due to blocked arteries. Viagra works by increaseing nitric oxide to dilate another artery.
An important enzyme (endothelial nitric oxide synthase-eNOS) produces nitric oxide from arginine. ADMA competes with arginine and “uncouples” eNOS to produce an oxidant-peroxynitrite-(ONOO). NO is essential to maintain arterial health. Peroxynitrite destroys arterial health. ADMA levels are increased in obesity and all other cardiovascular risk factors. Most cardiovascular healthcare professionals are aware of this relationship.
Arginine has another critical function in normal human health. When humans consume protein than is broken down into arginine and other amino acids, arginine activates the mechanistic target of rapamycin (mTOR) to coordinate food intake with growth in children. ADMA levels in kids vary with growth rates. This is a similar diagram to the one at the top, but here the left side (top) of the molecule is identical, and the right (bottom) is different. Metformin switches off mTOR by interfering with the nutrient sensing machinery that activates it. Arginine and ADMA use the same transporters to cross cellular membranes. It is highly likely that ADMA switches on mTOR and metformin produces its dramatic health benefits by blocking that activity. Most healthcare professionals are not aware of that relationship.
ADMA competes with arginine to reduce NO production and dramatically increase oxidants. It is highly likely that it also activates the nutrient sensing mechanism to switch on mTOR. Together, those two effects play a critical role in artery disease. Metformin blocks mTOR activation directly, probably by blocking ADMA effects at the level of a transporter-receptor (tranceptor).