Monitoring acute metabolic changes in the liver and kidneys induced by fructose and glucose using hyperpolarized [2-13 C]dihydroxyacetone

Abstract

Purpose: To investigate acute changes in glucose metabolism in liver and kidneys in vivo after a bolus injection of either fructose or glucose, using hyperpolarized [2-¹³ C]dihydroxyacetone.

Methods: Spatially registered, dynamic, multislice MR spectroscopy was acquired for the metabolic products of [2-¹³ C]dihydroxyacetone in liver and kidneys. Metabolism was probed in 13 fasted rats at three time points: 0, 70, and 140 min. At 60 min, rats were injected intravenously with fructose (n = 5) or glucose (n = 4) at 0.8 g/kg to initiate acute response. Controls (n = 4) did not receive a carbohydrate challenge.

Results: Ten minutes after fructose infusion, levels of [2-¹³ C]phosphoenolpyruvate and [2-¹³ C]glycerol-3-phosphate halved in liver: 51% (P = 0.0010) and 47% (P = 0.0001) of baseline, respectively. Seventy minutes later, levels returned to baseline. The glucose challenge did not alter the signals significantly, nor did repeated administration of the dihydroxyacetone imaging bolus. In kidneys, no statistically significant changes were detected after sugar infusion other than a 20% increase of the glycerol-3-phosphate signal between 10 and 80 min after fructose injection (P = 0.0028).

Conclusion: Hyperpolarized [2-¹³ C]dihydroxyacetone detects a real-time, transient metabolic response of the liver to an acute fructose challenge. Observed effects possibly include ATP depletion and changes in the unlabeled pool sizes of glycolytic intermediates. Magn Reson Med 77:65-73, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Keywords: dynamic nuclear polarization; gluconeogenesis; glycerol-3-phosphate; glycolysis; hyperpolarization; metabolic imaging; phosphoenolpyruvate.

Figure 1

Scheme of the metabolic fates of exogenously-injected fructose and hyperpolarized DHAc. DHAc = dihydroxyacetone, DHAP = dihydroxyacetone phosphate, F1P = fructose-1-phosphate, G3P = glycerol-3-phosphate, GA3P = glyceraldehyde-3-phosphate, PEP = phosphoenolpyruvate, hydr = DHAc hydrate.

Figure 2

Coronal anatomic reference showing the positioning of the 1-cm liver and kidney slabs and the contour of the liver (yellow) and kidneys (red). ¹H image was acquired using a 3D balanced steady-state free precession sequence.

Figure 3

Acute metabolic changes of the signal normalized to the signal DHAc hydrate detected in the liver (black line) and in the kidneys (red line, multiplied by a factor of five) in response to fructose load using hyperpolarized [2-¹³C]DHAc MRS with spectral-spatial RF excitation. (a) ¹³C-MR spectra of three injections of HP DHAc, each separated by 70 minutes in time. (b) As in (a), but with the additional bolus injection of a glucose solution (0.8 g/kg) ten minutes prior to the acquisition of the second DHAc spectra. (c) As in (a), but with the additional bolus injection of a fructose solution (0.8 g/kg) ten minutes prior to the acquisition of the second DHAc spectra. The concentration of glucose in blood was monitored every 10-20 minutes (Fig.4a). DHAc = dihydroxyacetone, G3P = glycerol-3-phosphate, PEP = phosphoenolpyruvate, hydr = DHAc hydrate.

Figure 4

Acute metabolic response of the liver and kidneys in vivo to fructose or glucose loading. (a) Time course of the glucose concentration in blood corrected for the increase in the total blood volume after each injection or infusion. Error bars show the standard deviation of the measurement across animals. The glucometer readings added a ± 30 mg/dl intrinsic variability not shown in this plot. (b) Liver results: Percentage change between the metabolites integrals at baseline and 10 minutes or 80 minutes after the carbohydrates infusion, which was administered 60 minutes after the baseline. (c) Kidneys results: Percentage change between the metabolites integrals at baseline and 10 minutes or 80 minutes after the carbohydrates infusion. Error bars correspond to the standard deviation of the mean. Statistical significance was only observed in the fructose group and indicated with one asterisk, *, (0.001 < P < 0.0167) or two, **, (P < 0.001). DHAc = dihydroxyacetone, G3P = glycerol-3-phosphate, PEP = phosphoenolpyruvate.

Figure 5

Example of the time-course of the integrals of the PEP, G3P and DHAc hydrate resonances. DHAc = dihydroxyacetone, G3P = glycerol-3-phosphate, PEP = phosphoenolpyruvate, hydr = DHAc hydrate.