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Publication
Genetic activation of pyruvate dehydrogenase alters oxidative substrate
selection to induce skeletal muscle insulin resistance.
Authors Rahimi Y, Camporez JP, Petersen MC, Pesta D, Perry RJ, Jurczak MJ, Cline GW,
Shulman GI
Submitted By Submitted Externally on 11/10/2015
Status Published
Journal Proceedings of the National Academy of Sciences of the United States of America
Year 2014
Date Published 11/1/2014
Volume : Pages 111 : 16508 - 13
PubMed Reference 25368185
Abstract The pyruvate dehydrogenase complex (PDH) has been hypothesized to link lipid
exposure to skeletal muscle insulin resistance through a glucose-fatty acid
cycle in which increased fatty acid oxidation increases acetyl-CoA
concentrations, thereby inactivating PDH and decreasing glucose oxidation.
However, whether fatty acids induce insulin resistance by decreasing PDH flux
remains unknown. To genetically examine this hypothesis we assessed relative
rates of pyruvate dehydrogenase flux/mitochondrial oxidative flux and
insulin-stimulated rates of muscle glucose metabolism in awake mice lacking
pyruvate dehydrogenase kinase 2 and 4 [double knockout (DKO)], which results in
constitutively activated PDH. Surprisingly, increased glucose oxidation in DKO
muscle was accompanied by reduced insulin-stimulated muscle glucose uptake.
Preferential myocellular glucose utilization in DKO mice decreased fatty acid
oxidation, resulting in increased reesterification of acyl-CoAs into
diacylglycerol and triacylglycerol, with subsequent activation of PKC-? and
inhibition of insulin signaling in muscle. In contrast, other putative mediators
of muscle insulin resistance, including muscle acylcarnitines, ceramides,
reactive oxygen species production, and oxidative stress markers, were not
increased. These findings demonstrate that modulation of oxidative substrate
selection to increase muscle glucose utilization surprisingly results in muscle
insulin resistance, offering genetic evidence against the glucose-fatty acid
cycle hypothesis of muscle insulin resistance.








Genes
SymbolDescription
Pdk2pyruvate dehydrogenase 2
Pdk4pyruvate dehydrogenase kinase 4

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