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. 2017 Apr;77(4):1429-1437.
doi: 10.1002/mrm.26245. Epub 2016 Apr 21.

Detection of Localized Changes in the Metabolism of Hyperpolarized Gluconeogenic Precursors 13 C-lactate and 13 C-pyruvate in Kidney and Liver

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Free PMC article

Detection of Localized Changes in the Metabolism of Hyperpolarized Gluconeogenic Precursors 13 C-lactate and 13 C-pyruvate in Kidney and Liver

Cornelius von Morze et al. Magn Reson Med. .
Free PMC article

Abstract

Purpose: The purpose of this study was to characterize tissue-specific alterations in metabolism of hyperpolarized (HP) gluconeogenic precursors 13 C-lactate and 13 C-pyruvate by rat liver and kidneys under conditions of fasting or insulin-deprived diabetes.

Methods: Seven normal rats were studied by MR spectroscopic imaging of both HP 13 C-lactate and 13 C-pyruvate in both normal fed and 24 h fasting states, and seven additional rats were scanned after induction of diabetes by streptozotocin (STZ) with insulin withdrawal. Phosphoenolpyruvate carboxykinase (PEPCK) expression levels were also measured in liver and kidney tissues of the STZ-treated rats.

Results: Multiple sets of significant signal modulations were detected, with graded intensity in general between fasting and diabetic states. An approximate two-fold reduction in the ratio of 13 C-bicarbonate to total 13 C 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: MRI of HP 13 C gluconeogenic precursors may advance diabetes research by clarifying organ-specific roles in abnormal diabetic metabolism. Magn Reson Med 77:1429-1437, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Keywords: diabetes; dynamic nuclear polarization; fasting; gluconeogenesis; streptozotocin.

Figures

FIG. 1
FIG. 1
Primary pathways of glucose recycling, glucose-lactate (Cori) and glucose-alanine cycles. The three dominant mobilized metabolites are shown in gray boxes. Potential molecular fates of 13C label originating at C1 of lactate or pyruvate are indicated in color, with intermediates routinely observable by means of HP 13C MRSI in blue, and typically invisible fates in red. LDH, lactate dehydrogenase; PDC, pyruvate dehydrogenase complex; ALT, alanine transaminase; PC, pyruvate carboxylase; PK, pyruvate kinase; GLU, glutamate; aKG, alpha-ketoglutarate; ASP, aspartate; PEP, phosphoenolpyruvate.
FIG. 2
FIG. 2
Graphical summary of methods for HP 13C MR experiments with 13C-lactate (A) and 13C-pyruvate (B). Each experiment consisted of both scans run successively in a single session. Each polarization buildup lasted ~1 h, followed by rapid dissolution and transfer to the MRI scanner, followed by intravenous injection into the rat and rapid data acquisition.
FIG. 3
FIG. 3
Coronal MRSI of HP [1-13C]lactate in fed rat. Localized spectra were integrated to produce 3D metabolite images (color) of lactate and HP products alanine and pyruvate, shown overlaid on 1H SSFP anatomic images (grayscale) using OsiriX. Volume renderings of 3D liver and kidney ROIs generated in OsiriX for data analysis are also shown.
FIG. 4
FIG. 4
In vivo HP 13C MR spectra obtained from liver (top row) and kidney (bottom row) slabs of a representative normal rat following injections of HP 13C-pyruvate, in both normal fed (left column) and fasting (right column) states. These spectra clearly depict the large reduction of 13C-bicarbonate signal detected in both organs with fasting. Spectra are zoomed to show the 13C-bicarbonate peak. Corresponding unzoomed spectra are also included as insets in each figure panel for reference. NMR signal magnitude is shown, by convention.
FIG. 5
FIG. 5
Sagittal images of HP 13C lactate-to-alanine ratio (color) overlaid on standard 1H images (grayscale), in baseline and post-STZ states. Lactate-to-alanine ratio increased by 61% in liver and 140% in kidney after STZ in this case.
FIG. 6
FIG. 6
Bar graphs summarizing key local effects of fasting and STZ diabetes on HP metabolite ratios for HP pyruvate (A–C) and lactate (D) experiments (*0.01 < P < 0.05; **P < 0.01). See text for details. Error bars represent standard error of the mean.
FIG. 7
FIG. 7
Bar graphs showing PEPCK expression levels in STZ-treated diabetic animals relative to vehicle-treated controls. PEPCK is markedly increased in both liver (A) and kidney (B) of STZ-treated diabetic rats. Real-time PCR was repeated three times and the data shown is the average of all three experiments.

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