New Research Advances the ADMA-Metformin Story in Diabetes and Related Diseases
A Totally New Mechanism of Action for Metformin
Asymmetric dimethylarginine (ADMA) affects your health from the day of conception until the day that you die. Dr. John Cooke at Stanford called it an “uber marker.”
“We and others have provided evidence for a ubiquitous mechanism of endothelial pathobiology shared by all risk factors and markers examined to date. This mechanism of endothelial derangement is mediated by an endogenous inhibitor of nitric oxide synthase (NOS), a molecule known as asymmetrical dimethylarginine (ADMA).”
The last post discussed checklist treatments for the metabolic syndrome and related complications. New science expands this metabolic syndrome concept to many chronic diseases. Deeper understanding means we can treat these diseases much more precisely and effectively. I mentioned that Gerald Reaven first described the relationships of these conditions and how they are related to insulin resistance. Now we can show how this all ties together at a deeper level. ADMA levels correlate very powerfully with the level of insulin resistance. Drs. Cooke, Reaven and colleagues described it like this: “the association between plasma ADMA concentrations and insulin resistance was of greater magnitude than that between SSPG concentration (the specific determinant of insulin resistance) and fasting plasma insulin concentration (a commonly used surrogate estimate of insulin resistance…. plasma ADMA concentrations were not increased in hypertensive patients unless they were also insulin resistant. Moreover, when a subgroup of insulin-resistant individuals with hypertension was treated with pharmacological therapy to increase insulin sensitivity, ADMA levels fell with no alterations in blood pressure”
New science unravels this relationship between ADMA, insulin resistance, cardiovascular risk factors and complications. mTOR is a master metabolic genetic switch that coordinates food availability with grow in the fetus and child. This new research shows that ADMA increases the amount of mTOR in cells and switches on mTOR. Switched on mTOR increases insulin resistance. That increased mTOR activity increases LDL cholesterol and triglyceride synthesis. It increases fat deposition in fat cells. mTOR stands for the mechanistic target of rapamycin. Rapamycin is an antibiotic found in nature that switches mTOR off. When ADMA and rapamycin are given together, the effect of ADMA to increase cholesterol, triglycerides and fat deposits is blocked. This study proves ADMA upregulates mTOR activity and signaling.
That is a critical medical fact. Rapamycin is the medication in the drug eluting heart artery stent that suppresses inflammation and scar formation to keep the stent open longer. Rapamycin slows organ transplant rejection and derivatives are used in cancer treatments. It slows aging and the development of age related diseases. ADMA makes us age more rapidly and develop chronic illnesses more quickly.
This is so important because ADMA and metformin are structural analogs that have been proven to neutralize each other at the level of a cellular membrane. Understanding this interaction is a key to understanding this fundamental fact. Genes that are essential to fetal development become less active in healthy young adults. ADMA is a critical piece of the epigenetic machinery that takes a fertilized human egg and regulates the genes to produce teeth, hair, and eyeballs in a healthy young adult human. ADMA is part of the mechanism that switches on genes at exactly the right place, and the right time, and with the right intensity to form a functional organ. Our genes are surrounded by proteins called histones. One of the amino acids in a histone protein is arginine. Adding two methyl groups (CH3) to the arginine in the histone creates asymmetric dimethylarginine which unravels the gene to switch it on and make it active. You can see the two methyl groups on the left of the ADMA structure above. A fetus that lacks the gene that methylates arginine only lasts a few days. Then when the gene has done its work, the histone protein breaks down and free ADMA enters the circulation.
This sounds crazy, but it is a fact. The newborn has a high ADMA level and these levels correlate with growth rate in children. They are lowest in healthy young adults. ADMA levels begin to increase and athletic capacity begins to decrease at about age 25. Infants have a high ADMA level, healthy young adults have the lowest and then old, sick people have high ADMA levels again. In fact, ADMA levels are increased in virtually all cardiovascular and related diseases including obesity, high blood pressure, diabetes, heart artery disease, heart attack, stroke, chronic kidney disease and congestive heart failure. Normal fetal growth and development produces ADMA in development. ADMA levels correlate with growth rate in children, but later in life ADMA makes the heart bigger and the arteries thicker. It still coordinates food with growth, but in this case, it damages the heart, arteries, and other organs. We can finally make sense of this relationship.
When the mother eats protein, digestion breaks it down into amino acids. Amino acids—including arginine—are the foods that switch on mTOR in the fetus through a Rag GTPase mechanism in the lysosome of the cell. Critical to this function is an arginine transceptor at the surface of the lysosome. A transceptor transports the amino acid and is also a receptor. When arginine engages the transceptor, it switches on mTOR. ADMA is also an amino acid that switches on mTOR at the level of this transceptor. Metformin and AMDA neutralize each other in a membrane dependent event. Metformin switches off mTOR in a Rag GTPase dependent manner, probably by blocking the effect of ADMA in activating the transceptor that switches on mTOR. Switching on mTOR changes the activity of many genes. That explains the broad benefits of metformin in multiple diseases achieved by switching off mTOR and downstream gene expression. Switching off mTOR decreases insulin resistance. By using the small inexpensive molecule metformin to very precisely block ADMA effects, new research can reveal a great deal about the epigenetics and molecular biology of chronic disease. This new research that proves ADMA activates mTOR is one of the most critical discoveries in medical history. It may be worth a Nobel prize.