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.

To ascertain whether the inability to suppress glucose production and increase glucose utilization in response to glucose infusion is an inherent characteristic of immature individuals, we determined glucose rate of appearance (R.) in minimally stressed, clinically stable, extremely premature infants ( -26-wk gestation) at two glucose infusion rates (6.2±0.4 and 9.5±0.5 mg/kg per min). We also assessed whether an increase in glucose delivery suppresses proteolysis by measuring the R. of phenylalanine and leucine. Glucose R. (and utilization) increased significantly at the higher glucose infusion rate (7.9±0.5 vs. 9.8±0.6 mg/kg per min). Glucose production persisted at the lower glucose infusion rate but was suppressed to nearly zero at the higher rate (1.7±0.5 vs. 0.3±0.1 mg/kg per min). Proteolysis was unaffected by the higher glucose infusion rate as reflected by no change in the rates of appearance of either phenylalanine (96±5 vs. 95±3 ,mol/kg per h) or leucine (285±20 vs. 283±14 ;mol/kg per h). Thus, clinically stable, extremely premature infants suppress glucose production and increase glucose utilization in response to increased glucose infusion, demonstrating no inherent immaturity of these processes. In contrast, increasing the rate of glucose delivery results in no change in whole body proteolysis in these infants. The regulation of proteolysis in this population remains to be defined. (J. Clin. Invest. 1993. 92:1752-1758

The primary effect of insulin on whole body protein metabolism in postnatal life is to reduce proteolysis. To assess the role of insulin in the regulation of protein metabolism in prenatal life, leucine kinetics were determined in the ovine fetus at baseline and in response to hyperinsulinemia. These measurements were made in each fetus in two different maternal states: ad libitum maternal feeding and after a 5-day maternal fast. Maternal fasting resulted in significant increases in baseline fetal leucine rate of appearance (Ra; 51.9 +/- 16.7 vs. 37.3 +/- 3.6 mumol/min, P < 0.05) and leucine oxidation (30.1 +/- 8.9 vs. 8.8 +/- 2.2 mumol/min, P < 0.05). Hyperinsulinemia, which was associated with significant increases in fetal glucose utilization, did not affect total fetal leucine R(a) or leucine release from fetal proteolysis in either maternal state. Under well-fed maternal conditions, hyperinsulinemia produced no changes in the fetal oxidative or nonoxidative disposal of leucine. In contrast, during maternal fasting, hyperinsulinemia reduced fetal leucine oxidation (11.0 +/- 3.7 vs. 31.1 +/- 8.9 mumol/min, P < 0.05) and increased the nonoxidative disposal of leucine (35.4 +/- 4.0 vs. 19.0 +/- 6.1 mumol/min, P < 0.05). This resulted in a change in the fetal leucine accretion rate from negative to positive (-20.9 +/- 7.5 vs. 7.5 +/- 6.7 mumol/min, P < 0.05). These results suggest that, under conditions of restricted maternal substrate intake, fetal hyperinsulinemia and the attendant increase in fetal glucose utilization are associated with increased protein synthesis rather than decreased protein breakdown, thereby improving fetal leucine carcass accretion.