Patients with isolated closed-head injuries are characterized by excessive nitrogen loss, hyperglycemia, and increased caloric demand. However, the relative contributions of specific metabolic events such as protein breakdown and synthesis or glucose production and utilization to the physiological changes prevalent during isolated closed-head injury remains unestablished. By use of isotopic dilutions of L-[1-13C]leucine and D-[3-3H]glucose, components of protein and glucose metabolism were examined in patients with isolated closed-head injury (n = 7). Normal overnight-fasted volunteers (n = 8) were also studied as a reference point for comparison. Despite prevailing hyperinsulinemia (29 +/- 5 microU/ml), head-injured patients had elevated plasma leucine concentrations (183 +/- 22 vs. 144 +/- 8 mumol/l), whole body proteolysis (331 +/- 44 vs. 150 +/- 7 mg.kg-1.h-1), protein synthesis (248 +/- 38 vs. 126 +/- 11 mg.kg-1.h-1), and amino acid oxidation (84 +/- 11 vs. 23 +/- 3 mg.kg-1.h-1). Therefore nitrogen loss normally associated with isolated closed-head injury is primarily due to an increase in the rate of whole body proteolysis, with a greater proportion of the resultant amino acids being oxidized for energy. Furthermore, head-injured patients were hyperglycemic (6.7 +/- 0.3 mumol/l) with increased rates of glucose turnover (an estimate of production and utilization) compared with the controls (4.0 +/- 0.7 vs. 2.5 +/- 0.2 mg.kg-1.min-1). Hence, these data suggest that head injury, even in the absence of peripheral trauma, induces a physiological state of accelerated metabolism associated with resistance to insulin action.