The physiological significance of the hyperglucagonemia that occurs in patients with many catabolic conditions is unclear. The effect of hyperglucagonemia on resting metabolicrate (RMR) was studied in six normal subjects. Infusion of somatostatin (SRIH; 500 μg/h for 210 min) resulted in a 5-fold decrease in plasma C-peptide and a 2-fold decrease in plasma insulin and glucagon concentrations, but did not change RMR significantly. When glucagon (0.2 μg/kg·h), was infused with SRIH (500 μg/h for 210 min), the decreases in plasma Cpeptide and insulin were similar to that during the infusion of SRIH alone, but plasma glucagon increased from 160 ± 24 (±SEM) to 560 ± 80 pg/mL (P < 0.001). There was a significant increase in RMR during the entire period (210 min) of glucagoninfusion (P < 0.01). During the last hour of the glucagon plus SRIH infusion, the RMR was 1.38 ± 0.10 Cal/min, which was 15% higher than the preinfusion RMR (1.19 ± 0.10 Cal/min; P < 0.01) and 14% higher than the RMR during the same period when SRIH alone was infused (1.21 ± 0.11 Cal/min; P < 0.01). When SRIH and glucagon were infused, protein oxidation (calculated from urinary nitrogen loss) was 52 ± 5 mg/min, 29% higher than when SRIH alone was infused (40 ± 5 mg/min; P < 0.05). These results indicate that hyperglucagonemia during insulin deficiency results in an increase in energy expenditure, which may contribute to the catabolic state in many conditions.