We have investigated the responsiveness of protein kinetics to insulin and the role of glucose oxidation rate as a mediator of the protein catabolic response to burn injury and sepsis by assessing the response of leucine and urea kinetics to a 5-h hyperinsulinemic euglycemic clamp with and without the simultaneous administration of dichloroacetate (DCA) (to further increase glucose oxidation via stimulation of pyruvate dehydrogenase activity) in eight severely burned and eight septic patients. Leucine and urea kinetics were measured by the primed-constant infusions of [1(-13)C]leucine and [15N2]urea. Compared with controls, basal leucine kinetics (flux and oxidation) were significantly elevated (P less than 0.01) in both groups of patients. Hyperinsulinemia elicited significant (P less than 0.05) decreases in leucine kinetics in both groups of patients. Consistent with this observation, hyperinsulinemia caused urea production to decrease significantly (P less than 0.05) in both patient groups. The administration of DCA to patients during hyperinsulinemia elicited a significant increase in glucose oxidation rate compared with the clamp rate (P less than 0.05), and the percent of glucose uptake oxidized increased from 45.5 +/- 5.5 to 53.5 +/- 4.8%; yet the response of leucine and urea kinetics to the clamp plus DCA was not different from the response to the clamp alone. These results suggest that the maximal effectiveness of insulin to suppress protein breakdown is not impaired and that a deficit in glucose oxidation or energy supply is probably not playing a major role in mediating the protein catabolic response to severe burn injury and sepsis.