In the present study, the plasma total BCAA concentration was maintained during the LY 334370 hydrochloride insulin infusion in the control group in a way that it was not different from that measured in the basal/postabsortive levels. However, in all of the previous reports the plasma BCAA concentrations decreased more than 50% relative to that at the basal/postabsorptive conditions during the insulin infusion creating a circumstance of a non-physiological ��control��. Therefore, the difference in whole-body GDR between amino acid infusion and control in these previous reports may relate in part to the greater rate of glucose disposal in the ��control�� experiments. By maintaining the overall plasma BCAA concentrations at the postabsorptive levels during the insulin infusion in the present study, we were able to clearly describe the role of the increase, per se, of the plasma BCAA concentrations on plasma glucose turnover. Given the lack of an effect of increased plasma BCAA on inducing insulin resistance in the present study, the negative correlation reported previously between plasma BCAA and insulin sensitivity in humans may reflect impaired ability to metabolize BCAA in insulin-resistant individuals. We have previously shown that the abundance of enzymes involved in the oxidation of BCAA in muscle is reduced in insulin-resistant individuals, and this can impair the utilization of BCAA leading to increased muscle and circulating BCAA levels. In addition to muscle, decreased activities or expression of key enzymes involved in BCAA catabolism in obesity/insulin-resistance have been reported in the liver and adipose tissue in animal models and in the visceral fat in humans. Increased concentrations of BCAA in Type 2 Diabetes have also been directly linked to decreased clearance of these amino acids from plasma. There is previously reviewed evidence indicating that in a metabolic environment where free fatty acid concentrations are increased, which is a general observation in obesity/insulinresistance, MES sodium salt branched-chain ketoacid dehydrogenase activity is decreased. Such observations can explain the negative correlation between plasma BCAA and insulin sensitivity, and where increased concentrations of BCAA are secondary to decreased ability to metabolize BCAA. Under these circumstances, and given that increased BCAA, per se, do not induce insulin resistance, increased plasma BCAA levels may be a ��metabolic marker�� of the metabolic environment associated with obesity and insulin resistance rather than a cause of insulin resistance.