The Effects of Long-Term Valsartan Treatment on Skeletal Muscle Fatty Acid Handling in Humans With Impaired Glucose Metabolism

Context: Blocking the renin-angiotensin system reduces the incidence of type 2 diabetes mellitus in humans with impaired glucose metabolism (IGM). Nevertheless, underlying mechanisms remain to be established. Objective: The purpose of this study was to investigate the effects of the angiotensin II type 1 receptor blocker valsartan (VAL) on skeletal muscle fatty acid (FA) handling in subjects with IGM. Design/Setting: This was a randomized, double-blind placebo-controlled trial at Maastricht University Medical Center. Intervention/Main Outcomes/Participants: Fasting and postprandial skeletal muscle FA handling were assessed at baseline and after 26 weeks of treatment with VAL or placebo in 26 subjects with IGM. Fasting and postprandial skeletal muscle FA handling were determined by combining the forearm balance technique with stable isotopes of palmitate. [H-2(2)]-Palmitate was infused iv to label endogenous triacylglycerol (TAG) and free fatty acid (FFA) in the circulation, and [U-C-13]-palmitate was incorporated in a high-fat mixed meal (2.6 MJ, 61% energy from fat) to label chylomicron TAG. Muscle biopsy samples were taken to determine im TAG, diacylglycerol (DAG), FFA, and phospholipid contents, their fractional synthetic rates and degree of saturation, and mRNA expression of oxidative genes. Results: VAL decreased saturation of im TAG and DAG fractions but did not affect net muscle uptake of [H-2(2)]-palmitate, very low-density lipoprotein ([H-2(2)])-TAG and chylomicron ([U-C-13])-TAG, and muscle mRNA expression. VAL decreased FA spillover, as estimated by circulating [U-C-13]-palmitate, and FFA rate of appearance and tended to decrease chylomicron TAG concentrations. Conclusions: VAL treatment for 26 weeks decreased saturation of skeletal muscle TAG and DAG stores, suggesting altered intramuscular lipid partitioning of FA. The VAL-induced reduction in postprandial FA spillover, endogenous lipolysis, and chylomicron TAG concentrations indicate improved adipose tissue lipid buffering capacity.