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Elevation of plasma concentrations of nonesterified fatty acids (NEFA) has been reported to result in protein sparing and in impaired insulin-mediated glucose metabolism. To assess the influence of the chain length of fatty acids on these effects, medium-chain (MC) and long-chain (LC) fatty acid-containing lipid emulsions (2 mg/kg/min each) combined with heparin were administered during 390 minutes to 25 healthy overnight-fasted male subjects. Whole body leucine flux (a parameter of whole body protein breakdown) decreased during MC triglycerides (MCT) by 20% (P <.005). Irreversible leucine catabolism (oxidation of [1-(13)C]-leucine) decreased during LC triglycerides (LCT) by 40% (P <.01) but not during MCT when compared to controls receiving glycerol infusions. MCT administration resulted in a marked (52 %, P <.001) decrease of alpha-ketoisocaproate (alpha-KIC) concentration, suggesting diminished leucine transamination and decreased leucine nonoxidative disappearance (P <.015). Hyperinsulinemia (30 to 40 microU/mL, euglycemic clamping) resulted in decreased leucine flux and oxidation during both lipid infusions, particularly during MCT. The increase in glucose disappearance during hyperinsulinemia in subjects receiving MCT or LCT was less than in controls, and endogenous glucose production measured by 6,6-D(2)-glucose infusions was less suppressed (P <.01). Thus, elevation of plasma LC fatty acids (but not of MC fatty acids) results in decreased leucine oxidation (protein catabolism). This protein-sparing effect of LCT appears to be dissociated from fatty acid effects on glucose metabolism; both MCT and LCT diminished insulin's ability to increase glucose disappearance and to decrease hepatic glucose production.