To simultaneously assess the relative antiproteolytic effect of insulin on both skeletal muscle and in the whole body, phenylalanine rates of appearance (Ra; reflecting proteolysis) were measured across the leg (reflecting skeletal muscle) and in the whole body, utilizing a constant tracer infusion of [2H5]phenylalanine in the basal state and during euglycemic hyperinsulinemia (2,600 microU/ml) in seven normal adults. Phenylalanine Ra in the leg was significantly decreased during hyperinsulinemia (6.11 +/- 0.83 vs 3.59 +/- 0.70 mumol/min, P less than 0.001). In contrast, leg phenylalanine rate of utilization (Rd) was not significantly changed (4.88 +/- 0.77 vs. 3.86 +/- 0.92 mumol/min). Phenylalanine Ra in the whole body was significantly decreased during hyperinsulinemia (49.4 +/- 2.2 vs. 41.9 +/- 2.3 mumol/min, P less than 0.001). However, phenylalanine release was suppressed to a significantly greater degree in release was suppressed to a significantly greater degree in the leg than in the whole body during hyperinsulinemia (43 +/- 7 vs. 15 +/- 2%, P less than 0.01). These results suggest that insulin suppresses proteolysis in the whole body and in skeletal muscle, even in the face of hypoaminoacidemia. In addition, the substantially greater degree of suppression of proteolysis by insulin in skeletal muscle compared with the whole body suggests that, at least under these conditions, insulin may have a greater antiproteolytic effect on skeletal muscle compared with other tissues.