Robert E. Shangraw

Bed-rest-induced insulin resistance occurs primarily in muscle

Treatment of trauma victims and patients with severe illness may contribute to their metabolic derangements by severely restricting physical activity. We sought to quantitate the impact of absolute bed rest alone on insulin regulation of glucose metabolism in six healthy subjects. Six to seven days of strict bed rest resulted in moderate deterioration in oral glucose tolerance and increased both fasting plasma insulin concentration and the insulin response to an oral glucose challenge by more than 40%. Euglycemic insulin clamp studies demonstrated the development of resistance to insulins stimulation of whole-body glucose utilization. This change was characterized by a rightward shift of the insulin dose-response curve (insulin concentration at which 50% of maximal stimulation occurred was 45 +/- 3 (SE) microU/mL in the base line period and 78 +/- 8 microU/mL after seven days of bed rest, P less than .01) with little alteration in the maximal response in the rate of glucose uptake (baseline 15.4 +/- 1.4 mg/kg.min and bed rest 14.0 +/- 1.3 mg/kg.min). In contrast to the shift of sensitivity of whole-body glucose utilization to insulin, suppression of hepatic glucose output by insulin was unchanged by seven days of bed rest. Insulin binding to circulating mononuclear cells was not changed by bed rest. These studies demonstrate that the limited physical activity dictated by bed rest for as little as seven days is associated with substantial resistance to insulins effects on glucose metabolism. Further, the data suggest that these effects occur primarily in skeletal muscle with little change in insulin action on the liver.

Lipolytic response to metabolic stress in critically ill patients.

ObjectiveTo measure whole-body lipolysis and fatty acid re-esterification in critically ill patients. DesignThe rates of appearance of glycerol and palmitic acid in blood plasma were measured by infusing stable isotope tracers [2H5]glycerol and [1-13C]palmitic acid, respectively. Energy expenditure was measured by indirect calorimetry. SettingMedical ICU of The University of Texas Medical Branch Hospital, a universitybased referral center. PatientsFive uninjured critically ill patients. Four patients were hospitalized because of respiratory insufficiency and one because of myocardial infarction. Three patients died during their hospitalization. InterventionsMetabolic studies were performed in each patient after an overnight (12-hr) fast. Measurements and Main ResultsMean ± SE glycerol and fatty acid rates of appearance were 4.5 ±1.0 and 11.5 ± 0.8 umol/kg-min, respectively. The ratio of fatty acid to glycerol rate of appearance was 2.9 ± 0.5. Resting energy expenditure was 132 ± 6% of predicted. ConclusionsAn accelerated rate of lipolysis is part of the metabolic response to severe stress, regardless of its etiology. Because the rate of fatty acid release far exceeded energy requirements, fatty acids that were not oxidized as fuel were re-esterified to triglyceride, presumably in the liver.

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

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.

Pharmacokinetics of Dichloroacetate in Patients Undergoing Liver Transplantation

Background Dichloroacetate (DCA) is an effective alternative to bicarbonate to treat lactic acidosis and stabilize acid-base homeostasis during liver transplantation. Although DCA presumably is metabolized by the liver, the impact of end-stage liver disease and liver transplantation on DCA distribution and elimination is unknown. Therefore, the pharmacokinetics of DCA were determined in patients with end-stage liver disease undergoing orthotopic liver transplantation. Methods Thirty-three patients undergoing liver transplantation were given DCA as two 40-mg/kg infusions over 60 min, the first after induction of anesthesia, the second 4 h later. Plasma DCA concentrations were determined by gas chromatography-mass spectroscopy. One- and two-compartment pharmacokinetic models were fitted to DCA concentrations versus time data using a mixed-effects population approach. Various models permitted changes in central compartment volume and/or plasma clearance to account for changes in hepatic mass and function and circulatory status during the paleohepatic, anhepatic, and neohepatic periods. Results The optimal model had two compartments. DCA clearance was 0.997, 0.0, and 1.69 ml *symbol* kg sup -1 *symbol* min sup -1 during the paleohepatic, anhepatic, and neohepatic periods, respectively (P < 0.05). Interindividual variability in central compartment volume differed during the paleohepatic and neohepatic periods. There was no apparent influence of blood or fluid requirements during surgery on DCA clearance or volume of distribution. Conclusions Absence of DCA clearance during the anhepatic period indicates that DCA is metabolized exclusively by the liver. Differences in interindividual variability in central compartment volume during the paleohepatic and neohepatic periods possibly result from physiologic changes during surgery. Finally, the results indicate that the newly transplanted liver eliminates DCA better than the native liver.

Oxygen metabolism during liver transplantation : The effect of dichloroacetate

Dichloroacetate (DCA) stimulates pyruvate dehydrogenase (PDH), accelerating recovery of the postischemic heart.Because DCA also stimulates hepatic PDH, it may facilitate graft recovery during liver transplantation (OLT). Hepatic removal and replacement during OLT produce major changes in O2 consumption (VO2), and return of baseline VO2 has been used to index early graft function. We examined the effect of DCA on O2 metabolism during OLT. Forty patients received DCA 80 mg/kg intravenously in divided doses, and 40 served as controls. Serial measurements were made for body temperature, hemodynamics, O2 metabolic indices, and plasma substrate and hormonal concentrations. Oxygen delivery (DO2 I) and consumption (VO2 I) indices were calculated. Patients exhibited stable hemodynamics, with similar fluid and blood product requirements. Compared with the dissection stage, DO2 I and VO2 I were decreased during the anhepatic stage (31% and 36%, respectively), then returned to dissection stage values soon after portal vein unclamping. Temperature decreased during the anhepatic stage and returned toward dissection stage value after graft perfusion. DCA reduced lactic acidosis and NaHCO3 use but did not alter hemodynamics or measures of O2 metabolism or body temperature. VO2 is decreased during the anhepatic stage largely due to loss of hepatic metabolism. Restoration of VO2 by 30 min after portal vein unclamping reflects rapid recovery of O2 metabolism by the graft liver, but DCA does not accelerate recovery of VO2. DCA does not seem to facilitate early graft hepatic function as indexed by VO2. Implications: We evaluated whether dichloroacetate, which stimulates pyruvate dehydrogenase, can accelerate recovery of graft liver hepatic function during liver transplantation, as indexed by oxygen consumption. We found that despite evidence that it activated pyruvate dehydrogenase, dichloroacetate did not affect recovery of transplanted liver function. (Anesth Analg 1997;85:746-52)

Massive Airway Edema after Azathioprine

AZATHIOPRINE is an antimetabolite widely used to suppress the immune system in recipients of organ transplants, as well as in patients with primary autoimmune disorders. Over the past 30 yr, it has proved to be an effective agent. However, multiple side effects have been reported, ranging in severity from fever and rash to cardiovascular collapse. 1,2 We report an acute idiosyncratic reaction to azathioprine in a patient undergoing kidney transplantation, characterized by life-threatening upper airway edema and circulatory collapse, both of which were elicited again after rechallenge.

MECHANISM OF DICHLOROACETATE-INDUCED HYPOLACTATEMIA IN HUMANS WITH OR WITHOUT CIRRHOSIS

Dichloroacetate (DCA) has been used as an experimental treatment for lactic acidosis because it lowers plasma lactic acid concentration. Three potential mechanisms could underlie the hypolactatemic action of DCA, but the dominant mechanism in vivo remains unclear. This study tested whether DCA-induced hypolactatemia occurs via decreased lactate production, increased lactate clearance, or decreased rate of glycolysis in healthy humans and in patients with end-stage cirrhosis. Cirrhosis is associated with decreased hepatic pyruvate dehydrogenase (PDH) content. Six healthy volunteers and 7 cirrhotic patients received a primed, constant infusion of 1-13C-pyruvate and 15N-alanine for 5 hours. DCA (35 mg/kg intravenously) was administered at 2 hours. Plasma isotopic enrichment was measured by gas chromatography/mass spectrometry (GC/MS), and exhaled CO2 enrichment by isotope ratio mass spectrometry. Pyruvate and alanine production rates (Ra) were determined by isotope dilution, and pyruvate oxidation calculated as 13CO2 production from 13C-pyruvate. Ra lactate was calculated as the difference between Ra pyruvate and its disposal by oxidation to CO2 and conversion to alanine. Baseline plasma lactate kinetics in cirrhotic patients did not differ from controls. DCA decreased lactate concentration in both groups by approximately 53%. DCA decreased glycolysis (Ra pyruvate) by 24%, increased the fraction of pyruvate oxidized to CO2 by 26%, and decreased pyruvate transamination to alanine by 25%. DCA also inhibited lactate production by 85%, but decreased plasma lactate clearance by 60% in both groups. DCA reduces plasma lactic acid concentration by inhibiting production, via stimulating pyruvate oxidation and inhibiting glycolysis, rather than increasing clearance. In addition, end-stage cirrhosis does not alter either the mechanism or the magnitude of the metabolic response to DCA.