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

  • Molecular and cellular mechanisms of disease
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

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.

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All data generated or analyzed during this study are included in this published article.

Abbreviations

IRS:

Insulin receptor substrate

IMCL:

Intramuscular lipid

T2DM:

Type 2 diabetes mellitus

DNP:

Dynamic nuclear polarization

PDH:

Pyruvate dehydrogenase

DCA:

Dichloroacetate

PFK:

Phosphofructokinase

G6P:

Glucose 6 phosphate

PGC-1α:

Peroxisome proliferator-activated receptor-γ coactivator 1α

PDK:

Pyruvate dehydrogenase kinase

DKO:

Double knock-out

ETC:

Electron transport chain

tC:

Total 13C signal

ALCAR:

Acetyl carnitine

AcAc:

Acetoacetate

LDH:

Lactate dehydrogenase

ALT:

Alanine aminotransferase

TCA:

Tricarboxylic acid

CrAT:

Carnitine acetyl transferase

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Funding

The study acknowledges funding support from the National Institutes of Health (NIH) CA176836, AA005965, AA018681, S10 OD012283, P41 EB015891 (DS); the US Department of Defense PC100427 (DS); NIH EB009070, DK106395, NS096575, CA213020 (DM); NIH R01NS107409 (JMP); the Welch Foundation I-2009–20190330 (JMP); DK095960, DK087307 (PH); the France-Berkeley Fund (TJ & DB); and California Department of Public Health 18–10923 (TJ).

Author information

Authors and Affiliations

  1. Advanced Imaging Research Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA

    Jae Mo Park

  2. Department of Radiology, Stanford University, 1201 Welch Rd., Stanford, CA, 94305, USA

    Jae Mo Park, Sonal Josan, Ralph E. Hurd & Daniel M. Spielman

  3. Neuroscience Program, SRI International, 333 Ravenswood Ave., Menlo Park, CA, 94025, USA

    Sonal Josan & Dirk Mayer

  4. Applied Science Laboratory, GE Healthcare, 333 Ravenswood Ave., Menlo Park, CA, 94025, USA

    Ralph E. Hurd

  5. Department of Molecular Biosciences, University of California Davis, 3426 Meyer Hall, Davis, CA, 95616, USA

    James Graham & Peter J. Havel

  6. CNRS, Aix-Marseille University, CRMBM, 13385, Marseille, France

    David Bendahan

  7. Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland, 22 S. Green St., Baltimore, MD, 21201, USA

    Dirk Mayer

  8. Department of Biochemistry and Molecular Medicine, University of California-Davis, 4323 Tupper Hall, Davis, CA, 95616, USA

    Youngran Chung & Thomas Jue

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  1. Jae Mo Park
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  10. Thomas Jue
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Contributions

JMP, REH, DM, DMS, and TJ contributed to the conception and design of research; JMP, SJ, REH, JG, DB, and TJ performed experiments; JMP, SJ, REH, JG, PH, DB, DM, YC, DMS, and TJ discussed, analyzed, and interpreted experiment data; JMP and TJ prepared figures, analyzed the data, wrote the drafts of the manuscript, and incorporated comments; JMP, SJ, REH, JG, PH, DB, DM, YC, DMS, and TJ reviewed and approved the final version of the manuscript.

Corresponding author

Correspondence to Thomas Jue.

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Park, J.M., Josan, S., Hurd, R.E. et al. Hyperpolarized NMR study of the impact of pyruvate dehydrogenase kinase inhibition on the pyruvate dehydrogenase and TCA flux in type 2 diabetic rat muscle. Pflugers Arch - Eur J Physiol 473, 1761–1773 (2021). https://doi.org/10.1007/s00424-021-02613-3

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