The aim of the present study was to evaluate the effect of prolonged inhibition of beta-oxidation on glucose and lipid muscle forearm metabolism and cGMP and endothelin-1 forearm release in patients with type 2 diabetes mellitus and ischemic cardiomyopathy. Fifteen patients were randomly allocated in a double blind cross-over parallel study with trimetazidine (20 mg tid) or placebo lasting 15 days. At the end of each period, all patients underwent euglycemic-hyperinsulinemic clamps with forearm indirect calorimetry and endothelial balance of vasodilator and vasoconstricor factors. Compared with placebo, trimetazidine induced 1) an increase in insulin-induced forearm glucose uptake and glucose oxidation accompained with a reduction in forearm lipid oxidation and citrate release and 2) a decrease of endothelin-1 release paralleled by a significant increase in forearm cGMP release. Forearm glucose oxidation significantly correlated with cGMP release (r=0.37, p<0.04) while forearm lipid oxidation positively correlated with endothelin-1 release (r=0.40, p<0.03). In conclusion, for the first time, we demonstrated that insulin induced-forearm glucose oxidation and forearm cGMP release were increased while forearm endothelin-1 release was decreased during trimetazidine treatment. Metabolic and vascular effects of trimetazidine in muscle add new interest in the use of trimetazidine in type 2 diabetic patients with cardiovascular disease.