Asymmetric dimethylarginine (ADMA) is a great example of this fact. Yesterday we discussed ADMA increasing with age and how it can cause arterial disease. The gene that makes the enzyme leading to ADMA production is absolutely essential in the fetus. If it is not present, the fetus dies within a few days. ADMA plays a key role in fetal development. ADMA levels are tightly correlated with growth in normal children.
High ADMA levels can have rapid effects. In patients with type 2 diabetes, drinking a milkshake (75% fat, 15% carbohydrate, 10% protein) increased ADMA levels two and a half times within five hours. The ability of an arm artery to dilate after the milkshake was one fourth of the fasting value. High fructose consumption increases ADMA levels.
ADMA activates mTOR and increases fat cell size. ADMA is formed from the amino acid arginine. It shares the same transporters as arginine. Arginine activates mTOR. Metformin and ADMA are structural analogs—their structure is similar enough that they block each other at the level of a cell membrane. They neutralize each other. Metformin inhibits mTOR directly by interfering with the nutrient sensing mechanism that detects amino acids like arginine. It is very likely that ADMA is a mechanism through which nutrients like fructose activate mTOR.
In the fetus and child, mTOR matches nutrient availability with growth—later in life nutrients also activate mTOR to cause growth. Excess nutrients all day long make the arteries thicker, and the heart bigger. They cause high blood pressure and heart disease. Increased ADMA levels contribute to other chronic illnesses like lung disease and cancer.
Genes that are essential to coordinate growth with nutrition supply in the fetus and child cause deadly disease when switched on inappropriately later in life. You can directly block that effect with metformin.
Normal Genes are Essential for Healthy Development: They Cause Chronic Disease Later in Life
Hi, Bill. I’ve been meaning to ask you to address human gene mapping and its relationship to predicting diseases, particularly heart disease, diabetes, and hypertension. I know there is a lot of work going on in Estonia and I believe Norway, as well as in England, on the use of human genome study for prediction of disease, even in those illnesses that may involve many, many genes, and thus complicate the effort. Your thoughts? Could be an area for you to tackle next.