PubMed1996
OBJECTIVE: To determine whether activation of pyruvate dehydrogenase with dichloroacetate can reverse sepsis-induced insulin resistance in humans or rats. DESIGN: Prospective, controlled study. SETTING: Intensive care unit (ICU) and laboratory at a university medical center. SUBJECTS: Nine patients were admitted to the ICU with Gram-negative sepsis, confirmed by cultures. In addition, chronically instrumented, Sprague-Dawley rats, either controls or with live Escherichia coli-induced sepsis. INTERVENTIONS: Hyperinsulinemic euglycemic clamp, with or without coadministration of dichloroacetate. MEASUREMENTS AND MAIN RESULTS: In humans, a primed, constant infusion of [6,6-2H2]glucose was used to determine endogenous glucose production and whole-body glucose disposal. Septic humans exhibited impaired maximal insulin-stimulated glucose utilization (39.5 +/- 2.7 mumol/kg/min), despite complete suppression of endogenous glucose production. In rats, a primed, constant infusion of [3-3H]glucose was used to determine endogenous glucose production and whole-body glucose disposal. Tissue glucose uptake in vivo was determined by [14C]-2-deoxyglucose uptake. Maximal, whole-body, insulin-stimulated glucose utilization was 205 +/- 11 and 146 +/- 9 mumol/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. CONCLUSIONS: Activation 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.