Effects of insulin and plasma amino acid concentration on leucine metabolism in humans. Role of substrate availability on estimate of whole body protein synthesis

We examined the effect of insulin and plasma amino acid concentrations on leucine kinetics in 15 healthy volunteers (age 22 ± 2 yrs) using the euglycemic insulin clamp technique and an infusion of [1-14C]leucine. Four different experimental conditions were examined: (a) study one, high insulin with reduced plasma amino acid concentrations; (b) study two, high insulin with maintenance of basal plasma amino acid concentrations; (c) study three, high insulin with elevated plasma amino acid concentrations; and (d) study four, basal insulin with elevated plasma amino acid concentrations. Data were analyzed using both the plasma leucine and alpha-ketoisocaproate (the alpha-ketoacid of leucine) specific activities. In study one total leucine flux, leucine oxidation, and nonoxidative leucine disposal (an index of whole body protein synthesis) all decreased (P < 0.01) regardless of the isotope model utilized. In study two leucine flux did not change, while leucine oxidation increased (P < 0.01) and nonoxidative leucine disposal was maintained at the basal rate; endogenous leucine flux (an index of whole body protein degradation) decreased (P < 0.01). In study three total leucine flux, leucine oxidation, and nonoxidative leucine disposal all increased (P < 0.001), while endogenous leucine flux decreased (P < 0.001). We conclude that: (a) hyperinsulinemia alone decreases plasma leucine concentration and inhibits endogenous leucine flux (protein breakdown), leucine oxidation, and nonoxidative leucine disposal (protein synthesis); (b) hyperaminoacidemia, whether in combination with hyperinsulinemia or with maintained basal insulin levels decreases endogenous leucine flux and stimulates both leucine oxidation and nonoxidative leucine disposal.