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Detecting Metabolism of Gluconeogenic Precursors Lactate and Pyruvate in Kidney & Liver with Hyperpolarized 13 C MRI
Author(s) -
Morze Cornelius,
Chang GeneYuan,
Larson Peder E,
Shang Hong,
Allu Prasanna KR,
Bok Robert A,
Crane Jason C,
Olson Marram P,
Tan Chou T,
MarcoRius Irene,
Nelson Sarah J,
Kurhanewicz John,
Pearce David,
Vigneron Daniel B
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.lb664
Subject(s) - endocrinology , medicine , phosphoenolpyruvate carboxykinase , gluconeogenesis , chemistry , diabetes mellitus , insulin , kidney , streptozotocin , alanine , bicarbonate , metabolism , pyruvic acid , biochemistry , enzyme , amino acid
Objective The objective of this study was to apply new methods in hyperpolarized (HP) 13C magnetic resonance imaging (MRI) to characterize tissue‐specific alterations in the metabolism of hyperpolarized HP gluconeogenic precursors 13C‐lactate and 13C‐pyruvate by rat liver and kidneys in vivo in both fasting and insulin deprivation in diabetes. Methods Solutions of 13C‐lactate and 13C‐pyruvate were magnetically hyperpolarized using the method of dissolution dynamic nuclear polarization (DNP), for use in spectroscopic MRI imaging of anesthetized rats. Seven normal rats were scanned by HP 13C MRI of both 13C‐lactate and 13C‐pyruvate in both normal fed and 24h fasting states, and seven additional rats were scanned after induction of diabetes by streptozotocin (STZ) with subsequent withdrawal of insulin (24–36h). Separate images of the injected substrates and their individual metabolic products (lactate, pyruvate, alanine, and bicarbonate) were acquired. Following the imaging experiments, phosphoenolpyruvate carboxykinase (PEPCK) expression levels were also measured in liver and kidney tissues of the STZ‐treated rats, and compared with seven vehicle‐treated controls. Results Multiple sets of significant metabolic modulations were detected, with graded intensity in general from fasting to diabetes ( Figure 1). An approximate two‐fold reduction in the ratio of 13C‐bicarbonate to total 13C signal was observed in both organs in fasting. The ratio of HP lactate‐to‐alanine was markedly altered, ranging from a liver‐specific 54% increase in fasting, to increases of 69% and 92% in liver and kidney, respectively, in diabetes. Diabetes resulted in a 40% increase in renal lactate signal. STZ resulted in 5.86‐fold and 2.73‐fold increases in PEPCK expression in liver and kidney, respectively. Conclusion The intermediary metabolism of gluconeogenic precursors 13C‐lactate and 13C‐pyruvate can be monitored non‐invasively in vivo using HP 13C MRI. Localized changes in the HP metabolic spectra of these probes in the liver and kidneys were detected in states of increasing gluconeogenic activity, with generally graded intensity of response from fasting to diabetes. These HP 13C methods could be extremely useful for non‐invasive monitoring of hepatic and renal components of gluconeogenesis in future preclinical and ultimately clinical studies. Support or Funding Information We gratefully acknowledge grant support from NIH K01DK099451, P41EB013598, and R01DK56695. We also acknowledge support from the Manning Foundation, a Ben J. Lipps Research Fellowship Award from the American Society of Nephrology, as well as T32DK007219.