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Regulation of hepatic fat and glucose oxidation in rats with lipid‐induced hepatic insulin resistance
Author(s) -
Alves Tiago C.,
Befroy Douglas E.,
Kibbey Richard G.,
Kahn Mario,
Codella Roberto,
Carvalho Rui A.,
Falk Petersen Kitt,
Shulman Gerald I.
Publication year - 2011
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.24170
Subject(s) - medicine , endocrinology , hyperinsulinemia , insulin resistance , insulin , glucose clamp technique , pyruvate dehydrogenase complex , flux (metallurgy) , lipid oxidation , biology , glucose uptake , gluconeogenesis , basal (medicine) , chemistry , pancreatic hormone , metabolism , biochemistry , enzyme , antioxidant , organic chemistry
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. (HEPATOLOGY 2011.)