Asymmetric dimethylarginine as a mediator of vascular dysfunction and a marker of cardiovascular disease and mortality: an intriguing interaction with diabetes mellitus

Asymmetric dimethylarginine (ADMA) has evolved as an important regulator of nitric oxide (NO) synthesis in recent years. Elevated levels of ADMA have been reported in many conditions associated with a high cardiovascular risk. Moreover, ADMA is a biomarker for major cardiovascular events and mortality in cohorts with high, intermediate and low overall cardiovascular risk. Discrepant data have been reported on cardiovascular risk in people with and without diabetes mellitus, and the association of ADMA with diabetes mellitus per se has also remained controversial, possibly relating to type and stage of diabetes. Clinical and experimental data suggest that there is a multifaceted link between ADMA and insulin metabolism and action on one hand, and ADMA and glucose utilisation on the other. This interplay may be regulated by the enzyme involved in the metabolic degradation of ADMA, dimethylarginine dimethylaminohydrolase (DDAH). Recent data from prospective clinical studies suggest that whilst ADMA may be a marker for total mortality in patients without diabetes, elevated ADMA may exert beneficial effects in patients with diabetes. In this respect, ADMA could serve as a re-coupling agent overcoming endothelial nitric oxide synthase (eNOS) uncoupling in patients with diabetes. Anticipated advances in clinical and experimental investigation will help us to better understand this complex interrelationship between diabetes, eNOS, DDAH and ADMA.