The ADMA-Metformin Hypothesis: Linking the Cardiovascular Consequences of the Metabolic Syndrome and Type 2 Diabetes

Abstract

Metformin and asymmetric dimethylarginine (ADMA) are structural analogs. They have opposite effects at multiple points on complex signaling pathways that coordinate energy, molecular synthesis, growth, and metabolism with nutrient intake. Excess saturated fats and glucose may initiate the methylation of arginine residues in proteins involved in the transcription of genes mediating inflammation, cell proliferation, apoptosis, and oncogenesis. Free ADMA may appear in the circulation after proteolysis of these proteins when the work of transcription is complete and ADMA subsequently functions as a signaling molecule. In children, ADMA levels are not significantly related to the usual metabolic syndrome risk factors but instead there is a significant association between ADMA and alkaline phosphatase - a marker of normal growth. There is only one direct study that shows that ADMA negates the metabolic effects of metformin. There are no investigations that demonstrate that metformin blocks the effect of ADMA and so this review must be considered hypothesis generating. The potential implications of the metformin-ADMA relationship merit further investigation.