ObjectiveTo determine whether activation of pyruvate dehydrogenase with dichloroacetate can reverse sepsis-induced insulin resistance in humans or rats.DesignProspective, controlled study.SettingIntensive care unit (ICU) and laboratory at a university medical center.SubjectsNine patients were admitted to the ICU with Gramnegative sepsis, confirmed by cultures. In addition, chronically instrumented, Sprague-Dawley rats, either controls or with live Escherichia coli-induced sepsis.InterventionsHyperinsulinemic euglycemic clamp, with or without coadministration of dichloroacetate.Measurements and Main ResultsIn humans, a primed, constant infusion of [6,6-sup 2 H2]glucose was used to determine endogenous glucose production and whole-body glucose disposal. Septic humans exhibited impaired maximal insulin-stimulated glucose utilization (39.5 plus minus 2.7 micro mol/kg/min), despite complete suppression of endogenous glucose production. In rats, a primed, constant infusion of [3-sup 3 H]glucose was used to determine endogenous glucose production and whole-body glucose disposal. Tissue glucose uptake in vivo was determined by [sup 14 C]-2-deoxyglucose uptake. Maximal, whole-body, insulin-stimulated glucose utilization was 205 plus minus 11 and 146 plus minus 9 micro mol/kg/min in control and septic rats, respectively. The defect was specific to skeletal muscle and heart. Stimulation of pyruvate dehydrogenase with dichloroacetate caused a 50% decrease in plasma lactate concentration but failed to improve whole-body insulin-stimulated glucose utilization in either the septic human or rat. Dichloroacetate reversed the impairment of insulin-stimulated myocardial glucose uptake in septic rats, but did not influence skeletal muscle glucose uptake either under basal conditions or during insulin stimulation.ConclusionsActivation of pyruvate dehydrogenase with dichloroacetate does not ameliorate the impairment of whole-body, insulin-stimulated glucose uptake in septic humans or rats, or reverse the specific defect in insulin-mediated skeletal muscle glucose uptake by septic rats. Therefore, the decreased pyruvate dehydrogenase activity associated with sepsis does not appear to mediate sepsis-induced insulin resistance during insulin-stimulated glucose uptake at either the whole-body or tissue level.(Crit Care Med 1996; 24:566-574)