AMINO-ACIDS ENHANCE INSULIN RESISTANCE TO EXOGENOUS GLUCOSE-INFUSION IN OVERNIGHT-FASTED HUMANS

The role that amino acids play in regulating exogenous glucose infusion during hyperinsulinemia was examined in overnight-fasted volunteers. Each study consisted of both a 30-minute basal period and a 4-hour experimental period during which insulin was infused at either 0.6, 1.2, 2.5, 5.0, 10, or 20 mU/kg/min with euglycemia maintained. Two protocols were used. In the first (I), subjects were allowed to develop hypoaminoacidemia, and in the second (II), plasma amino acid levels were maintained near basal by frequently monitoring plasma leucine levels in conjunction with exogenous infusion of an L-amino acid solution. The amount of amino acids infused were 0.85 +/- 0.11, 1.53 +/- 0.17, 1.97 +/- 0.13, 2.18 +/- 0.50, 2.78 +/- 0.61, and 2.83 +/- 0.44 mg/kg/min at escalating insulin doses, respectively. When amino acids were infused, the amount of glucose required to maintain euglycemia was lower at each insulin dose used (4.5 +/- 0.3 vs 3.6 +/- 0.4, 7.6 +/- 0.5 vs 6.9 +/- 0.3, 10.4 +/- 1.0 vs 8.7 +/- 0.5*, 13.3 +/- 0.8 vs 10.2 +/- 0.4*, 14.7 +/- 0.8 vs 11.7 +/- 0.6*, and 14.9 +/- 0.6 vs 11.8 +/- 0.8* mg/kg/min at escalating insulin doses, respectively; * p < 0.05). The calculated maximal infusion rates were 15.8 +/- 0.6 vs 12.6 +/- 0.4 mg/kg/min (protocol I vs II, p < 0.001), while the concentrations required to achieve half-maximal rates were 153 +/- 22 and 134 +/- 22-mu-U/ml (p = ns), respectively. These data indicate that amino acid infusions to attain near basal plasma concentrations during a hyperinsulinemic euglycemic clamp in overnight-fasted normal volunteers resulted in decreased responsiveness, without altering sensitivity, to insulin's effects on exogenous glucose infusion. This is suggestive of an amino acid-mediated postreceptor defect.