Hyperpolarized NMR study of the impact of pyruvate dehydrogenase kinase inhibition on the pyruvate dehydrogenase and TCA flux in type 2 diabetic rat muscle

Jae Mo Park, Sonal Josan, Ralph E. Hurd, James Graham, Peter J. Havel, David Bendahan, Dirk Mayer, Youngran Chung, Daniel M. Spielman, Thomas Jue

Research output: Contribution to journalArticlepeer-review

Abstract

The role of pyruvate dehydrogenase in mediating lipid-induced insulin resistance stands as a central question in the pathogenesis of type 2 diabetes mellitus. Many researchers have invoked the Randle hypothesis to explain the reduced glucose disposal in skeletal muscle by envisioning an elevated acetyl CoA pool arising from increased oxidation of fatty acids. Over the years, in vivo NMR studies have challenged that monolithic view. The advent of the dissolution dynamic nuclear polarization NMR technique and a unique type 2 diabetic rat model provides an opportunity to clarify. Dynamic nuclear polarization enhances dramatically the NMR signal sensitivity and allows the measurement of metabolic kinetics in vivo. Diabetic muscle has much lower pyruvate dehydrogenase activity than control muscle, as evidenced in the conversion of [1-13C]lactate and [2-13C]pyruvate to HCO3 and acetyl carnitine. The pyruvate dehydrogenase kinase inhibitor, dichloroacetate, restores rapidly the diabetic pyruvate dehydrogenase activity to control level. However, diabetic muscle has a much larger dynamic change in pyruvate dehydrogenase flux than control. The dichloroacetate-induced surge in pyruvate dehydrogenase activity produces a differential amount of acetyl carnitine but does not affect the tricarboxylic acid flux. Further studies can now proceed with the dynamic nuclear polarization approach and a unique rat model to interrogate closely the biochemical mechanism interfacing oxidative metabolism with insulin resistance and metabolic inflexibility.

Original languageEnglish (US)
Pages (from-to)1761-1773
Number of pages13
JournalPflugers Archiv European Journal of Physiology
Volume473
Issue number11
DOIs
StatePublished - Nov 2021

Keywords

  • Dichloroacetate
  • Hyperpolarized NMR
  • Lactate
  • Metabolism
  • Skeletal muscle
  • Type 2 diabetes

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Physiology (medical)

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