Context:Blocking the renin-angiotensin system reduces the incidence of diabetes mellitus in humans with impaired glucose metabolism (IGM). underlying mechanisms remain to be established.Objective:The purpose of study was to investigate the effects of the angiotensin II type 1 blocker valsartan (VAL) on skeletal muscle fatty acid (FA) handling in with IGM.Design/Setting:This was a randomized, double-blind placebo- trial at Maastricht University Medical Center.Intervention/Main Outcomes/Participants:Fasting and postprandial skeletal muscle FA assessed at baseline and after 26 weeks of treatment with VAL or placebo subjects with IGM. Fasting and postprandial skeletal muscle FA handling determined by combining the forearm balance technique with stable palmitate. [2H2]-Palmitate was infused iv to label endogenous (TAG) and free fatty acid (FFA) in the circulation, and [U-13C]- incorporated in a high-fat mixed meal (2.6 MJ, 61% energy from fat) to chylomicron TAG. Muscle biopsy samples were taken to determine im TAG, diacylglycerol (DAG), FFA, and phospholipid contents, their fractional rates and degree of saturation, and mRNA expression of oxidative genes.Results:VAL decreased saturation of im TAG and DAG fractions but affect net muscle uptake of [2H2]-palmitate, very low-density ([2H2])-TAG and chylomicron ([U-13C])-TAG, and muscle mRNA expression. decreased FA spillover, as estimated by circulating [U-13C]-palmitate, rate of appearance and tended to decrease chylomicron TAG concentrations.Conclusions:VAL treatment for 26 weeks decreased skeletal muscle TAG and DAG stores, suggesting altered intramuscular partitioning of FA. The VAL-induced reduction in postprandial FA endogenous lipolysis, and chylomicron TAG concentrations indicate adipose tissue lipid buffering capacity.