Glucose and leucine metabolism in 18 severely burned patients were studied using the primed constant infusion of U-13C-glucose and 1-13C-leucine, respectively. The leucine data were used to calculate rates of whole-body protein synthesis. In four additional burn patients and seven normal controls, the effects of exogenously infused insulin on the metabolism of infused glucose were evaluated. Also, the effect on leucine metabolism of adding insulin to infused glucose was tested and rates of protein synthesis were calculated. The protein studies were divided into two groups depending on the rate of glucose infusion. Protein synthesis was 4.3 + 0.54 g protein/kg/day during the lower infusion rates (1.4--4.5 mg/kg/min) and 5.17 + 0.19 g protein/kg/day during the higher infusion rates (4.7--9.3 mg/kg/min) (statistically different, p less than 0.05). However, when the high infusion rate group was divided into two subgroups (high, 4.7--6.8 mg/kg/min, and very high, 7.03--9.31 mg/kg/min), there was no difference in the rate of protein synthesis. When U-13C-glucose was infused during varying rates of unlabeled glucose infusion, we found that the per cent of CO2 coming from the direct oxidation of glucose rose rapidly at the lower infusion rates but reached a plateau at approximately 55% as the infusion rates exceeded 5 mg/kg/min. Addition of insulin did not affect the rate of glucose oxidation but did seem to exert a stimulatory effect on protein synthesis. It was concluded that there appears to be a maximal rate of glucose infusion, beyond which physiologically significant increases in protein synthesis and direct oxidation of glucose cannot be expected. Furthermore, there appears to be a physiological cost of exceeding the optimal glucose infusion rate, as indicated by increased rates of CO2 production during infusion as well as large fat deposits in the liver at autopsy in patients infused with large amounts of glucose.