Pyruvate dehydrogenase inactivity is not responsible for sepsis-induced insulin resistance

Robert Shangraw, Farook Jahoor, Robert R. Wolfe, Charles H. Lang

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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 coil-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 end whole-body glucose disposal. Septic humans exhibited impaired maximal insulin-stimulated glucose utilization (39.5 ± 2.7 μmol/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 μmol/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.

Original languageEnglish (US)
Pages (from-to)566-574
Number of pages9
JournalCritical Care Medicine
Volume24
Issue number4
DOIs
StatePublished - Apr 1996

Fingerprint

Pyruvic Acid
Insulin Resistance
Sepsis
Oxidoreductases
Glucose
Insulin
Skeletal Muscle
Intensive Care Units
Escherichia
Glucose Clamp Technique
Deoxyglucose
Sprague Dawley Rats
Lactic Acid

Keywords

  • critica l illness
  • dichloroacetate
  • hyperglycemia
  • infection
  • insulin
  • insulin resistance
  • lactate
  • pyruvate dehydrogenase
  • sepsis

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Pyruvate dehydrogenase inactivity is not responsible for sepsis-induced insulin resistance. / Shangraw, Robert; Jahoor, Farook; Wolfe, Robert R.; Lang, Charles H.

In: Critical Care Medicine, Vol. 24, No. 4, 04.1996, p. 566-574.

Research output: Contribution to journalArticle

Shangraw, Robert ; Jahoor, Farook ; Wolfe, Robert R. ; Lang, Charles H. / Pyruvate dehydrogenase inactivity is not responsible for sepsis-induced insulin resistance. In: Critical Care Medicine. 1996 ; Vol. 24, No. 4. pp. 566-574.
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abstract = "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 coil-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 end whole-body glucose disposal. Septic humans exhibited impaired maximal insulin-stimulated glucose utilization (39.5 ± 2.7 μmol/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 μmol/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.",
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N2 - 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 coil-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 end whole-body glucose disposal. Septic humans exhibited impaired maximal insulin-stimulated glucose utilization (39.5 ± 2.7 μmol/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 μmol/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.

AB - 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 coil-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 end whole-body glucose disposal. Septic humans exhibited impaired maximal insulin-stimulated glucose utilization (39.5 ± 2.7 μmol/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 μmol/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.

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KW - lactate

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KW - sepsis

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