An intravenous glucose tolerance test (IVGTT) was administered in both lean (n = 9) and obese (n = 14) volunteers to ascertain the importance of the dynamic interactions between insulin and glucose on plasma concentrations of two amino acids known to be primarily used by skeletal muscle, namely leucine and isoleucine, and one amino acid, phenylalanine, which is primarily metabolized by the liver. After a 30-minute basal period, each subject received a bolus injection of glucose (0.3 g/kg IV) followed 20 minutes later by a bolus injection of tolbutamide (300 mg). Blood samples were drawn frequently for 180 minutes after the glucose infusion to determine plasma concentrations of glucose, insulin, leucine, isoleucine, and phenylalanine. Plasma glucose and insulin concentrations during the basal period were increased by 10% and 100%, respectively, in obese compared with lean individuals (P < .05), whereas phenylalanine, isoleucine, and leucine levels were similar between groups. During the IVGTT, plasma glucose level initially increased by twofold and slowly returned to basal level thereafter, whereas insulin level responded to glucose and tolbutamide infusions in a typical biphasic manner. Plasma leucine and isoleucine levels did not change from basal levels during the first 60 minutes of the IVGTT as hyperglycemic hyperinsulinemia prevailed in both groups. However, when plasma glucose had returned to near-basal levels, plasma leucine and isoleucine levels began to decrease, reaching a plateau of approximately 20% and 35% below basal, and plasma insulin level remained elevated in the lean and obese individuals, respectively. In contrast to the two branched-chain amino acids, phenylalanine level remained unchanged throughout the entire experimental period in both lean and obese subjects. During the IVGTT, a resistance to insulin-mediated glucose and protein metabolism was observed in the obese individuals, as evidenced by elevated glucose to insulin, leucine to insulin, isoleucine to insulin, and phenylalanine to insulin ratios. Therefore, during dynamic changes in plasma insulin and glucose levels, hyperglycemia appears to exert an opposing force to insulin's effect on amino acid and protein metabolism, which may be important during dynamic physiologic conditions such as diabetes, stress, trauma, or mealtime. © 1994.