title: Pyruvate dehydrogenase inactivity is not responsible for sepsis-induced insulin resistance.
abstract: OBJECTIVE
  To determine whether activation of pyruvate dehydrogenase with dichloroacetate can reverse sepsis-induced insulin resistance in humans or rats.
  
  
  METHODS
  Prospective, controlled study.
  
  
  METHODS
  Intensive care unit (ICU) and laboratory at a university medical center.
  
  
  METHODS
  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.
  
  
  METHODS
  Hyperinsulinemic euglycemic clamp, with or without coadministration of dichloroacetate.
  
  
  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.
authors.affiliation: Department of Anesthesiology, Oregon Health Sciences University, Portland 97201-3098, USA.
authors.forename: R E
authors.initials: RE
authors.lastname: Shangraw
authors.forename: F
authors.initials: F
authors.lastname: Jahoor
authors.forename: R R
authors.initials: RR
authors.lastname: Wolfe
authors.forename: C H
authors.initials: CH
authors.lastname: Lang
mesh_terms: D018806:APACHE; D000328:Adult; D000818:Animals; D003999:Dichloroacetic Acid / Q000627:therapeutic use; D004341:Drug Evaluation; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011768:Pyruvate Dehydrogenase Complex / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D011768:Pyruvate Dehydrogenase Complex; D003999:Dichloroacetic Acid; D005947:Glucose