Article

Regulation of hepatic fat and glucose oxidation in rats with lipid-induced hepatic insulin resistance.

Department of Internal Medicine, Yale University School of Medicine, New Haven, CT; Department of Biochemistry, Faculty of Sciences and Technology, University of Coimbra, Portugal.
Hepatology (impact factor: 11.66). 01/2011; 53(4):1175-81. DOI:10.1002/hep.24170 pp.1175-81
Source: PubMed

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. CONCLUSION: 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.

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    Article: Pyruvate dehydrogenase activities during the fed-to-starved transition and on re-feeding after acute or prolonged starvation.
    M J Holness, M C Sugden
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    ABSTRACT: We investigated the temporal relationship between hepatic glycogen depletion and cardiac and hepatic PDH (pyruvate dehydrogenase complex) activities during the acute phase of starvation. There was a striking correlation between the decline in hepatic glycogen and PDH inactivation during the first 10 h of starvation. Re-feeding after 6 h starvation was associated with complete re-activation of PDH in liver and re-activation to approx. 75% of the fed value in heart, whereas in rats previously starved for 24-48 h re-activation was delayed in liver and diminished in heart. The results are discussed with reference to the fate of dietary carbohydrate after re-feeding.
    Biochemical Journal 04/1989; 258(2):529-33. · 4.90 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

3 weeks
 
awake rats
 
chronic lipid-induced hepatic insulin resistance
 
critical role
 
fasting V(PDH)
 
fatty acid oxidation
 
hepatic glucose
 
hepatic insulin resistance
 
high-fat diet
 
hyperglycemic clamp
 
hyperinsulinemia
 
hyperinsulinemic-euglycemic clamp
 
hyperinsulinemic-hyperglycemic clamp
 
increase V(PDH)
 
individual effects
 
lipid-induced hepatic insulin resistance
 
plasma glucose concentration
 
Pyruvate dehydrogenase
 
pyruvate dehydrogenase flux
 
tricarboxylic acid flux