Whole body protein turnover and energy expenditure before and during an oral glucose tolerance test (1 g/kg body wt) were studied on separate occasions in six healthy young men before and during 3 days of simulated microgravity using the 6 degrees head-down tilt (HDT) method. After 42-47 h of HDT, basal insulin concentrations increased significantly from 9.4 +/- 1.9 to 13.1 +/- 0.1 microU/ml (P < 0.002). No significant differences in glycemia, insulinemia, or free fatty acid concentrations were observed in response to the oral glucose load. With HDT, increases were observed in basal postabsorptive resting metabolic rate (8%; P < 0.05), lipid oxidation (33 +/- 2 to 51 +/- 5 mg/min; P < 0.02), and the thermic effect of glucose (7.7 +/- 1 to 10.7 +/- 0.6%; not significant). Protein turnover (arithmetic mean of ammonia and urea flux rates) was unchanged by HDT, but a significant increase was seen when calculated from ammonia alone (P < 0.02). The present data show that HDT results in an increased energy requirement through elevations in both the basal metabolic rate and the thermic response to food ingestion. These changes may have been brought about by a cephalic shift of body fluids similar to that experienced in microgravity.