Pyruvate dehydrogenase inactivity is not responsible for sepsis-induced insulin resistance
Shangraw, R.E.; Jahoor, F.; Wolfe, R.R.; Lang, C.H.
Critical Care Medicine 24(4): 566-574
1996
ISSN/ISBN: 0090-3493 PMID: 8612405 Document Number: 468922
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 (6,6-2H-2)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 mu-mol/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 mu-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. Conclusions: Activation of pyruvate dehydrogenase with dichloroacetate does not ameliorate the impairment of wholebody, 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 sepals does not appear to mediate sepsis-induced insulin resistance during insulin-stimulated glucose uptake at either the whole-body or tissue level.