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Proc Natl Acad Sci U S A. 2014 Nov 18;111(46):16508-13. doi: 10.1073/pnas.1419104111. Epub 2014 Nov 3.

Genetic activation of pyruvate dehydrogenase alters oxidative substrate selection to induce skeletal muscle insulin resistance.

Author information

1
Departments of Internal Medicine and Cellular & Molecular Physiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510.
2
Departments of Internal Medicine and.
3
Departments of Internal Medicine and Cellular & Molecular Physiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510 gerald.shulman@yale.edu.

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-θ 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.

KEYWORDS:

diacylglycerol; insulin action; liquid chromatography mass spectrometry; nuclear magnetic resonance; protein kinase C theta

PMID:
25368185
PMCID:
PMC4246337
DOI:
10.1073/pnas.1419104111
[Indexed for MEDLINE]
Free PMC Article

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