Elevations of plasma methylarginines in obesity and ageing are related to insulin sensitivity and rates of protein turnover

Aims/hypothesis: Increased circulating methylarginines ( MA) have been linked to the metabolic syndrome to explain endothelial dysfunction and cardiovascular disease risk. Proteins that contain MA are regulatory and release them during catabolism. We hypothesised that increased protein turnover in insulin-resistant states contributes to an increase in circulating MA. Materials and methods: We performed hyperinsulinaemic, euglycaemic, and isoaminoacidaemic experiments on 49 lean, obese and elderly subjects, with measurements of the kinetics of glucose and protein metabolism. Plasma MA, i.e. asymmetrical dimethylarginine ( ADMA), symmetrical dimethylarginine (SDMA), and N-G-monomethyl-L-arginine ( NMMA), lipids and body composition were measured. Results: Insulin resistance of glucose and protein metabolism occurred in obese and elderly subjects. ADMA concentrations were 29 to 120% higher in obese and 34% higher in elderly than in lean subjects. SDMA were 34 and 20% higher in obese than in lean and than in elderly subjects, respectively. NMMA were 32% higher in obese than in lean subjects. ADMA differed by sex, being higher in men, namely by 1.75 x in obese men and by 1.27 x in elderly men. Postabsorptive ADMA ( r= 0.71), SDMA ( r= 0.46), and NMMA ( r= 0.31) correlated ( all p< 0.05) with rates of protein flux. All three MA correlated negatively with clamp glucose infusion rates and uptake ( p< 0.001). ADMA and SDMA correlated negatively with net protein synthesis and clamp amino acid infusion rates p< 0.05). All MA also correlated with adiposity indices and fasting insulin and triglycerides ( p< 0.05). Conclusions/ interpretation: Obesity, sex and ageing affect MA. Elevations of the three MA in obese, and of ADMA in elderly men, are related to increased protein turnover and to lesser insulin sensitivity of protein metabolism. These interrelationships might amplify insulin resistance and endothelial dysfunction.