Glucose homeostasis in men fasted for 84 h was assessed using isotopes, indirect calorimetry and forearm balance techniques during a basal period and three sequential hyperinsulinaemic euglycaemic clamps each lasting for 150 min. Two protocols (n = 12 in each) were used: subjects were either allowed to develop hypoaminoacidaemia or received a commercial solution of L-amino acids while maintaining near-basal plasma leucine levels. Insulin infusions resulted in 3-, 35- and 650-fold increases in plasma insulin levels in both protocols. The infusion of amino acids produced a rightward shift in the dose-response curve of insulin's effect on suppressing hepatic glucose production, indicating decreased sensitivity in addition to blunting of the maximal responsiveness. Total body glucose rate of disappearance was progressively increased with escalating insulin doses, but was 22% lower at the intermediate and highest insulin doses in the group that was infused with amino acids (3.44 +/- 0.53 vs 4.82 +/- 0.71 and 7.72 +/- 1.01 vs 10.36 +/- 1.08 mg.kg-1.min-1, respectively; p less than 0.05). Forearm balance data confirmed the isotopic data, since amino acid infusions blunted the insulin-mediated increase in net forearm glucose utilization (by 50-83%). Furthermore, the infusion of amino acids resulted in marked reductions in the rate of carbohydrate oxidation and storage as assessed by indirect calorimetry. The data indicate that the amino acid-mediated suppression of glucose utilization and carbohydrate oxidation is exerted on the responsive component of insulin action.