Display options
Share it on

Exp Physiol. 2021 Dec;106(12):2412-2422. doi: 10.1113/EP089782. Epub 2021 Nov 15.

Hyperpolarized [1-.

Experimental physiology

Mads Bisgaard Bengtsen, Esben Søvsø Szocska Hansen, Rasmus Stilling Tougaard, Mads Dam Lyhne, Nikolaj Fibiger Rittig, Julie Støy, Niels Jessen, Christian Østergaard Mariager, Hans Stødkilde-Jørgensen, Niels Møller, Christoffer Laustsen

Affiliations

  1. Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus N, Denmark.
  2. The MR Research Center, Aarhus University Hospital, Aarhus N, Denmark.
  3. Department of Cardiology, Aarhus University Hospital, Aarhus N, Denmark.
  4. Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus N, Denmark.

PMID: 34705304 DOI: 10.1113/EP089782

Abstract

NEW FINDINGS: What is the central question of this study? Is it possible to combine the hyperpolarized magnetic resonance technique and the hyperinsulinaemic clamp method in order to evaluate skeletal muscle metabolism in a large animal model? What is the main finding and its importance? The logistical set-up is possible, and we found substantial increments in glucose infusion rates representing skeletal muscle glucose uptake but no differences in ratios of [1-

ABSTRACT: In skeletal muscle, glucose metabolism is tightly regulated by the reciprocal relationship between insulin and adrenaline, with pyruvate being at the intersection of both pathways. Hyperpolarized magnetic resonance (hMR) is a new approach to gain insights into these pathways, and human trials involving hMR and skeletal muscle metabolism are imminent. We aimed to combine the hyperinsulinaemic clamp technique and hMR in a large animal model resembling human physiology. Fifteen anaesthetized pigs were randomized to saline (control group), hyperinsulinaemic euglycaemic clamp technique (HE group) or hyperinsulinaemic hypoglycaemic clamp technique (HH group). Skeletal muscle metabolism was evaluated by hyperpolarized [1-

© 2021 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.

Keywords: glucose metabolism; homeostasis; insulin; skeletal muscle

References

  1. Ardenkjaer-Larsen, J. H., Fridlund, B., Gram, A., Hansson, G., Hansson, L., Lerche, M. H., Servin, R., Thaning, M., & Golman, K. (2003). Increase in signal-to-noise ratio of > 10,000 times in liquid-state NMR. Proceedings of the National Academy of Sciences of the United States of America, 100, 10158-10163. https://doi.org/10.1073/pnas.1733835100 - PubMed
  2. Bengtsen, M. B., Støy, J., Rittig, N. F., Voss, T. S., Magnusson, N. E., Svart, M. V., Jessen, N., & Møller, N. (2020). A human randomized controlled trial comparing metabolic responses to single and repeated hypoglycemia in type 1 diabetes. Journal of Clinical Endocrinology and Metabolism, 105, dgaa645. https://doi.org/10.1210/clinem/dgaa645 - PubMed
  3. Bergstrom, J. (1975). Percutaneous needle biopsy of skeletal muscle in physiological and clinical research. Scandinavian Journal of Clinical and Laboratory Investigation, 35, 609-616. https://doi.org/10.1080/00365517509095787 - PubMed
  4. DeFronzo, R. A., & Tripathy, D. (2009). Skeletal muscle insulin resistance is the primary defect in type 2 diabetes. Diabetes Care, 32, 157-162. https://doi.org/10.2337/dc09-s302 - PubMed
  5. DeFronzo, R. A., Tobin, J. D., & Andres, R. (1979). Glucose clamp technique: A method for quantifying insulin secretion and resistance. The American Journal of Physiology, 237, E214-E223. https://doi.org/10.1152/ajpendo.1979.237.3.e214 - PubMed
  6. Gilda, J. E., & Gomes, A. V. (2013). Stain-Free total protein staining is a superior loading control to β-actin for Western blots. Analytical Biochemistry, 440, 186-188. https://doi.org/10.1016/j.ab.2013.05.027 - PubMed
  7. Gjedsted, J., Buhl, M., Nielsen, S., Schmitz, O., Vestergaard, E. T., Tønnesen, E., & Møller, N. (2011). Effects of adrenaline on lactate, glucose, lipid and protein metabolism in the placebo controlled bilaterally perfused human leg. Acta Physiologica, 202, 641-648. https://doi.org/10.1111/j.1748-1716.2011.02316.x - PubMed
  8. Gradel, A. K. J., Kildegaard, J., Ludvigsen, T. P., Porsgaard, T., Schou-Pedersen, A. M. V., Fels, J. J., Lykkesfeldt, J., & Refsgaard, H. H. F. (2020). The counterregulatory response to hypoglycaemia in the pig. Basic & Clinical Pharmacology & Toxicology, 127(4), 278-286. https://doi.org/10.1111/bcpt.13422 - PubMed
  9. Halestrap, A. P., & Price, N. T. (1999). The proton-linked monocarboxylate transporter (MCT) family: Structure, function and regulation. The Biochemical Journal, 343(Pt 2), 281-299. http://www.ncbi.nlm.nih.gov/pmc/articles/pmc1220552/ - PubMed
  10. Hansen, E. S. S., Tougaard, R. S., Nørlinger, T. S., Mikkelsen, E., Nielsen, P. M., Bertelsen, L. B., Bøtker, H. E., Jørgensen, H. S., & Laustsen, C. (2017). Imaging porcine cardiac substrate selection modulations by glucose, insulin and potassium intervention: A hyperpolarized [1-13C]pyruvate study. NMR in Biomedicine, 30(6), 10.1002/nbm.3702. https://doi.org/10.1002/nbm.3702 - PubMed
  11. Heinicke, K., Dimitrov, I. E., Romain, N., Cheshkov, S., Ren, J., Malloy, C. R., & Haller, R. G. (2014). Reproducibility and absolute quantification of muscle glycogen in patients with glycogen storage disease by 13C NMR spectroscopy at 7 Tesla. PLoS One, 9(10), e108706. https://doi.org/10.1371/journal.pone.0108706 - PubMed
  12. Høieggen, A., Fossum, E., Moan, A., Rostrup, M., Eide, I. K., & Kjeldsen, S. E. (1999). Increased forearm blood flow during glucose clamp is related neither to insulin sensitivity nor to hyperinsulinemia in borderline hypertensive young men. Blood Pressure, 4, 227-230. https://doi.org/10.1080/080370599439616 - PubMed
  13. Jensen, J., Rustad, P. I., Kolnes, A. J., & Lai, Y. C. (2011). The role of skeletal muscle glycogen breakdown for regulation of insulin sensitivity by exercise. Frontiers in Physiology, 2, 112. https://doi.org/10.3389/fphys.2011.00112 - PubMed
  14. Jin, E. S., Moreno, K. X., Wang, J. X., Fidelino, L., Merritt, M. E., Sherry, A. D., & Malloy, C. R. (2016). Metabolism of hyperpolarized [1-(13)C]pyruvate through alternate pathways in rat liver. NMR in Biomedicine, 29(4), 466-474. https://doi.org/10.1002/nbm.3479. Epub 2016 Feb 2. PMID: 26836042; PMCID: PMC4805436. - PubMed
  15. Juel, C., & Halestrap, A. (1999). Lactate transport in skeletal muscle - role and regulation of the monocarboxylate transporter. The Journal of Physiology, 517(3), 633-642. https://doi.org/10.1111/j.1469-7793.1999.0633s.x - PubMed
  16. Keshari, K. R., Sriram, R., van Criekinge, M., Wilson, D. M., Wang, Z. J. Vigneron, D. B., Peehl, D. M., & Kurhanewicz, J. (2013). Metabolic reprogramming and validation of hyperpolarized 13C lactate as a prostate cancer biomarker using a human prostate tissue slice culture bioreactor. The Prostate, 73, 1171-1181. https://doi.org/10.1002/pros.22665 - PubMed
  17. Khegai, O., Schilte, R. F., Janich, M. A., Menzel, M. I., Farrell, E., Otto, A. M., Ardenkjaer-Larsen, J. H., Glaser, S. J., Haase, A., Schwaiger, M., & Wiesinger, F. (2014). Apparent rate constant mapping using hyperpolarized [1-13C]pyruvate. NMR in Biomedicine, 27, 1256-1265. https://doi.org/10.1002/nbm.3174 - PubMed
  18. Lauritzen, M. H., Laustsen, C., Butt, S. A., Magnusson, P., Søgaard, L. V., Ardenkjaer-Larsen, J. H., & Åkeson, P. (2013). Enhancing the [13C]bicarbonate signal in cardiac hyperpolarized [1-13C]pyruvate MRS studies by infusion of glucose, insulin and potassium. NMR in Biomedicine, 26, 1496-1500. https://doi.org/10.1002/nbm.2982 - PubMed
  19. Leftin, A., Degani, H., & Frydman, L. (2013). In vivo magnetic resonance of hyperpolarized [13C1]pyruvate: Metabolic dynamics in stimulated muscle. American Journal of Physiology. Endocrinology and Metabolism, 305, E1165-E1171. https://doi.org/10.1152/ajpendo.00296.2013 - PubMed
  20. Manell, E., Jensen-Waern, M., & Hedenqvist, P. (2017). Anaesthesia and changes in parameters that reflect glucose metabolism in pigs - a pilot study. Laboratory Animals, 51(5), 509-517. https://doi.org/10.1177/0023677216682773 - PubMed
  21. Miró, O., Barrientos, A., Alonso, J. R., Casademont, J., Jarreta, D., Urbano-Márquez, A., & Cardellach, F. (1999). Effects of general anaesthetic procedures on mitochondrial function of human skeletal muscle. European Journal of Clinical Pharmacology, 55(1), 35-41. https://doi.org/10.1007/s002280050589 - PubMed
  22. Mose, M., Rittig, N., Mikkelsen, U. R., Jessen, N., Bengtsen, M. B., Christensen, B., Jørgensen, J., & Møller, N. (2020). A model mimicking catabolic inflammatory disease; a controlled randomized study in humans. PLoS One, 15(11), e0241274. https://doi.org/10.1371/journal.pone.0241274 - PubMed
  23. Park, J. M., Hackett, E. P., Harrison, C. E., Reed, G. D., Chhabra, A. & Malloy, C. R. (2020). Effects of anaerobic exercise in skeletal muscle measured by hyperpolarized [1-13C]pyruvate in humans. ISMRM and SMRT, Virtual conference and exhibition, 8-14 August 2020. abstract nummer 3000. URL: https://www.ismrm.org/20/program_files/DP07-01.htm - PubMed
  24. Nielsen, P. M., Mariager, C. Ø., Mølmer, M., Sparding, N., Genovese, F., Karsdal, M. A., Nørregaard, R., & Laustsen, C. (2020). Hyperpolarized [1-13C] alanine production: A novel imaging biomarker of renal fibrosis. Magnetic Resonance in Medicine, 84(4), 2063-2073. https://doi.org/10.1002/mrm.28326. Epub 2020 May 25. PMID: 32452096 - PubMed
  25. Shulman, G. I., Rothman, D. L., Jue, T., Stein, P., DeFronzo, R. A., & Shulman, R. G. (1990). Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy. The New England Journal of Medicine, 322(4), 223-228. https://doi.org/10.1056/NEJM199001253220403 - PubMed
  26. Swanson, K. S., Mazur, M. J., Vashisht, K., Rund, L. A., Beever, J. E., Counter, C. M., & Schook, L. B. (2004). Genomics and clinical medicine: Rationale for creating and effectively evaluating animal models. Experimental Biology and Medicine, 229(9), 866-875. https://doi.org/10.1177/153537020422900902 - PubMed
  27. Thiebaud, D., Jacot, E., DeFronzo, R. A., Maeder, E., Jequier, E., & Felber, J. P. (1982). The effect of graded doses of insulin on total glucose uptake, glucose oxidation, and glucose storage in man. Diabetes, 31(11), 957-963. https://doi.org/10.2337/diacare.31.11.957 - PubMed
  28. Torchi, A., Serres, S., Cooper, A., Mallinson, J., McGing, J., Lobo, D. N., Cooper, A., Awais, R., Årstad, E., Glaser, M., Twyman, F., Gowland, P., Auer, D., Greenhaff, P. L., Faas, H. & Morris, P. (2019). Monitoring muscle metabolism non-invasively with dynamic nuclear polarisation magnetic resonance. WMIC 2019 in Montreal, 4-8 September 2019. Abstract number 538, URL: https://www.xcdsystem.com/wmis/program/wtcFzZf/index.cfm?pgid=1223 - PubMed
  29. Zöllner, F. G., Daab, M., Sourbron, S. P., Schad, L. R., Schoenberg, S. O., & Weisser, G. (2016). An open source software for analysis of dynamic contrast enhanced magnetic resonance images: UMMPerfusion revisited. BMC Medical Imaging, 16, 7. https://doi.org/10.1186/s12880-016-0109-0 - PubMed

Publication Types

Grant support