title: Regulation of hepatic fat and glucose oxidation in rats with lipid-induced hepatic insulin resistance.
abstract: Pyruvate dehydrogenase plays a critical role in the regulation of hepatic glucose and fatty acid oxidation; however, surprisingly little is known about its regulation in vivo. In this study we examined the individual effects of insulin and substrate availability on the regulation of pyruvate dehydrogenase flux (V(PDH) ) to tricarboxylic acid flux (V(TCA) ) in livers of awake rats with lipid-induced hepatic insulin resistance. V(PDH) /V(TCA) flux was estimated from the [4-(13) C]glutamate/[3-(13) C]alanine enrichments in liver extracts and assessed under conditions of fasting and during a hyperinsulinemic-euglycemic clamp, whereas the effects of increased plasma glucose concentration on V(PDH) /V(TCA) flux was assessed during a hyperglycemic clamp in conjunction with infusions of somatostatin and insulin to maintain basal concentrations of insulin. The effects of increases in both glucose and insulin on V(PDH) /V(TCA) were examined during a hyperinsulinemic-hyperglycemic clamp. The effects of chronic lipid-induced hepatic insulin resistance on this flux were also examined by performing these measurements in rats fed a high-fat diet for 3 weeks. Using this approach we found that fasting V(PDH) /V(TCA) was reduced by 95% in rats with hepatic insulin resistance (from 17.2 ± 1.5% to 1.3 ± 0.7%, P < 0.00001). Surprisingly, neither hyperinsulinemia per se or hyperglycemia per se were sufficient to increase V(PDH) /V(TCA) flux. Only under conditions of combined hyperglycemia and hyperinsulinemia did V(PDH) /V(TCA) flux increase (44.6 ± 3.2%, P < 0.0001 versus basal) in low-fat fed animals but not in rats with chronic lipid-induced hepatic insulin resistance.
  
  
  CONCLUSIONS
  These studies demonstrate that the combination of both hyperinsulinemia and hyperglycemia are required to increase V(PDH) /V(TCA) flux in vivo and that this flux is severely diminished in rats with chronic lipid-induced hepatic insulin resistance.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT; Department of Biochemistry, Faculty of Sciences and Technology, University of Coimbra, Portugal.
authors.forename: Tiago C
authors.initials: TC
authors.lastname: Alves
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Befroy
authors.forename: Richard G
authors.initials: RG
authors.lastname: Kibbey
authors.forename: Mario
authors.initials: M
authors.lastname: Kahn
authors.forename: Roberto
authors.initials: R
authors.lastname: Codella
authors.forename: Rui A
authors.initials: RA
authors.lastname: Carvalho
authors.forename: Kitt
authors.initials: K
authors.lastname: Falk Petersen
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002952:Citric Acid Cycle / Q000187:drug effects; D004041:Dietary Fats / Q000008:administration & dosage; D005223:Fats / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D005223:Fats; D011768:Pyruvate Dehydrogenase Complex; D005947:Glucose