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1. Magnetic resonance imaging as a noninvasive adjunct to conventional assessment of functional differences between kidneys in vivo and during ex vivo normothermic machine perfusion

Author

Hamelink, Tim L., Ogurlu, Baran, Pamplona, Carolina C., Castelein, Johannes, Bennedsgaard, Sigrid S., Qi, Haiyun, Weiss, Thomas, Lantinga, Veerle A., Pool, Merel B.F., Laustsen, Christoffer, Jespersen, Bente, Leuvenink, Henri G.D., Ringgaard, Steffen, Borra, Ronald J.H., Keller, Anna K., and Moers, Cyril

Published
2024
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2. The detection of acute kidney injury with hyperpolarized 13C Urea and multi-exponential fitting

Author

Grist, James T, Mariager, Christian Østergaard, Qi, Haiyun, Nielsen, Per Mose, and Laustsen, Christoffer

Subjects
Physics - Medical Physics
Abstract

Purpose: To assess the utility of Laplacian fitting to describe the differences in hyperpolarized 13C urea T2 relaxation in ischemic and healthy rodent kidneys. Theory and Methods: Six rats with unilateral renal ischemia were investigated. 13C urea T2 mapping was undertaken with a radial fast spin echo method, with subsequent post-processing performed with regularised Laplacian fitting. Results: Simulations showed that Laplacian fitting was stable down to a signal to noise ratio of 20. In vivo results showed a significant increase in the mono- and decrease in bi-exponential pools in IRI kidneys, in comparison to healthy (14+-10% vs 4+-2%, 85+-10% vs 95+-3%, p<0.05). Conclusion: We demonstrate, for the first time, the differences in multi-exponential behaviour of 13C,15N2-urea between the healthy and ischemic rodent kidney. The distribution of relaxation pools were found to be both visually and numerically significantly different. The ability to improve the information level in hyperpolarized MR, by utilizing the relaxation contrast mechanisms is an appealing option, that can easily be adopted in large animals and even in clinical studies in the near future., Comment: 14 pages, 4 figures

Published
2019

3. Magnetic resonance imaging as a non-invasive adjunct to conventional assessment of functional differences between kidneys in vivo and during ex vivo normothermic machine perfusion

Author

Hamelink, Tim L., primary, Ogurlu, Baran, additional, Pamplona, Carolina C., additional, Castelein, Johannes, additional, Bennedsgaard, Sigrid S., additional, Qi, Haiyun, additional, Weiss, Thomas, additional, Lantinga, Veerle A., additional, Pool, Merel B.F., additional, Laustsen, Christoffer, additional, Jespersen, Bente, additional, Leuvenink, Henri G.D., additional, Ringgaard, Steffen, additional, Borra, Ronald J.H., additional, Keller, Anna K., additional, and Moers, Cyril, additional

Published
2024
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5. 211.4: Magnetic resonance imaging assessment of functional differences between kidneys in vivo and during ex vivo normothermic machine perfusion

Author

Hamelink, Tim, primary, Lantinga, Veerle, additional, Ogurlu, Baran, additional, Pamplona, Carol, additional, Bennedsgaard, Sigrid, additional, Qi, Haiyun, additional, Castelein, Johannes, additional, Eijken, Marco, additional, Jaynes, Chris, additional, Dydak, Ulrike, additional, Jespersen, Bente, additional, Leuvenink, Henri, additional, Hansen, Esben, additional, Laustsen, Christopher, additional, Ringgaard, Stephen, additional, Keller, Anna Krarup, additional, Borra, Ronald, additional, and Moers, Cyril, additional

Published
2023
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9. The number of glomeruli and pyruvate metabolism is not strongly coupled in the healthy rat kidney

Author

Bech, Sabrina Kahina, Qi, Haiyun, Mariager, Christian Østergaard, Hansen, Esben Søvsø Szocska, Ilicak, Efe, Zöllner, Frank G, and Laustsen, Christoffer

Subjects
urogenital system, sex, renal, hyperpolarization, MRI
Abstract

PURPOSE: The number of glomeruli is different in men and women, as they also present different prevalence and progression of chronic kidney disease. A recent study has demonstrated a potential difference in renal metabolism between sexes, and a potential explanation could be the differences in glomeruli number. This study investigates the potential correlation between glomerular number and pyruvate metabolism in healthy kidneys.METHODS: This study is an experimental study with rats (N = 12). We used cationized-ferritin MRI to visualize and count glomeruli and hyperpolarized [1-13 C]pyruvate to map the metabolism. Dynamic contrast-enhanced MRI was used to analyze kidney hemodynamics using gadolinium tracer.RESULTS: Data showed no or subtle correlation between the number of glomeruli and the pyruvate metabolism. Minor differences were observed in the number of glomeruli (female = 24,509 vs. male = 26 350; p = .16), renal plasma flow (female = 606.6 vs. male= 455.7 ml/min/100 g; p = .18), and volume of distribution (female = 87.44 vs. male = 76.61 ml/100 ml; p = .54) between sexes. Mean transit time was significantly prolonged in males compared with females (female = 8.868 s vs. male = 10.63 s; p = .04).CONCLUSION: No strong statistically correlation between the number of glomeruli and the pyruvate metabolism was found in healthy rat kidneys.

Published
2022

13. Remodeling after myocardial infarction and effects of heart failure treatment investigated by hyperpolarized [1‐ 13 C]pyruvate magnetic resonance spectroscopy

Author

Tougaard, Rasmus Stilling, primary, Laustsen, Christoffer, additional, Lassen, Thomas Ravn, additional, Qi, Haiyun, additional, Lindhardt, Jakob Lykke, additional, Schroeder, Marie, additional, Jespersen, Nichlas Riise, additional, Hansen, Esben Søvsø Szocska, additional, Ringgaard, Steffen, additional, Bøtker, Hans Erik, additional, Kim, Won Yong, additional, Stødkilde‐Jørgensen, Hans, additional, and Wiggers, Henrik, additional

Published
2021
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17. Remodeling after myocardial infarction and effects of heart failure treatment investigated by hyperpolarized [1‐13C]pyruvate magnetic resonance spectroscopy.

Author

Tougaard, Rasmus Stilling, Laustsen, Christoffer, Lassen, Thomas Ravn, Qi, Haiyun, Lindhardt, Jakob Lykke, Schroeder, Marie, Jespersen, Nichlas Riise, Hansen, Esben Søvsø Szocska, Ringgaard, Steffen, Bøtker, Hans Erik, Kim, Won Yong, Stødkilde‐Jørgensen, Hans, and Wiggers, Henrik

Subjects
HEART failure, NUCLEAR magnetic resonance spectroscopy, MYOCARDIAL infarction, PYRUVATES, TREATMENT failure, METABOLIC clearance rate, ATOMIZERS
Abstract

Purpose: Hyperpolarized [1‐13C]pyruvate MRS can measure cardiac metabolism in vivo. We investigated whether [1‐13C]pyruvate MRS could predict left ventricular remodeling following myocardial infarction (MI), long‐term left ventricular effects of heart failure medication, and could identify responders to treatment. Methods: Thirty‐five rats were scanned with hyperpolarized [1‐13C]pyruvate MRS 3 days after MI or sham surgery. The animals were re‐examined after 30 days of therapy with β‐blockers and ACE‐inhibitors (active group, n = 12), placebo treatment (placebo group, n = 13) or no treatment (sham group, n = 10). Furthermore, heart tissue mitochondrial respiratory capacity was assessed by high‐resolution respirometry. Metabolic results were compared between groups, over time and correlated to functional MR data at each time point. Results: At 30 ± 0.5 days post MI, left ventricular ejection fraction (LVEF) differed between groups (sham, 77% ± 1%; placebo, 52% ± 3%; active, 63% ± 2%, P <.001). Cardiac metabolism, measured by both hyperpolarized [1‐13C]pyruvate MRS and respirometry, neither differed between groups nor between baseline and follow‐up. Three days post MI, low bicarbonate + CO2/pyruvate ratio was associated with low LVEF. At follow‐up, in the active group, a poor recovery of LVEF was associated with high bicarbonate + CO2/pyruvate ratio, as measured by hyperpolarized MRS. Conclusion: In a rat model of moderate heart failure, medical treatment improved function, but did not on average influence [1‐13C]pyruvate flux as measured by MRS; however, responders to heart failure medication had reduced capacity for carbohydrate metabolism. [ABSTRACT FROM AUTHOR]

Published
2022
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19. Assessment of mouse liver [1-13C]pyruvate metabolism by dynamic hyperpolarized MRS

Author

Faarkrog Høyer, Kasper, Laustsen, Christoffer, Ringgaard, Steffen, Qi, Haiyun, Mariager, Christian Østergaard, Nielsen, Thomas Svava, Sundekilde, Ulrik Kræmer, Treebak, Jonas T., Jessen, Niels, Stødkilde-Jørgensen, Hans, Faarkrog Høyer, Kasper, Laustsen, Christoffer, Ringgaard, Steffen, Qi, Haiyun, Mariager, Christian Østergaard, Nielsen, Thomas Svava, Sundekilde, Ulrik Kræmer, Treebak, Jonas T., Jessen, Niels, and Stødkilde-Jørgensen, Hans

Abstract

Hyperpolarized [1-13C]pyruvate magnetic resonance (MR) spectroscopy has the unique ability to detect real-time metabolic changes in vivo owing to its high sensitivity compared with thermal MR and high specificity compared with other metabolic imaging methods. The aim of this study was to explore the potential of hyperpolarized MR spectroscopy for quantification of liver pyruvate metabolism during a hyperinsulinemic isoglycemic clamp in mice. Hyperpolarized [1-13C]pyruvate was used for in vivo MR spectroscopy of liver pyruvate metabolism in mice. Mice were divided into two groups: i) non-stimulated 5-hour fasted mice and ii) hyperinsulinemic isoglycemic clamped mice. During clamp conditions, insulin and donor blood were administered at a constant rate whereas glucose were infused to maintain isoglycemia. When steady state was reached, insulin-stimulated mice were rapidly infused with hyperpolarized [1-13C]pyruvate for real-time tracking of the dynamic distribution of metabolic derivatives from pyruvate, such as [1-13C]lactate, [1-13C]alanine, and [13C]bicarbonate. Isotopomer analysis of plasma glucose confirmed 13C-incorporation from [1-13C]pyruvate into glucose was increased in fasted mice compared with insulin-stimulated mice, demonstrating an increased gluconeogenesis in fasted mice. The AUC ratios for [1-13C]alanine/[1-13C]pyruvate (38.2%), [1-13C]lactate/[1-13C]pyruvate (41.8%), and [13C]bicarbonate/[1-13C]pyruvate (169%) all increased significantly during insulin stimulation. Hyperpolarized [1-13C]pyruvate can be used for in vivo MR spectroscopy of liver pyruvate metabolism during hyperinsulinemic isoglycemic clamp conditions. Under these conditions, insulin decreased gluconeogenesis and increased [1-13C]alanine, [1-13C]lactate, and [13C]bicarbonate after a [1-13C]pyruvate bolus. This application of in vivo spectroscopy has the potential to identify impairments in specific metabolic pathways in the liver associated with obesity, insulin resistance, and non-a

Published
2019

21. Hyperpolarized 13 C,15 N2 -urea T2 relaxation changes in acute kidney injury

Author

Mariager, Christian Østergaard, Nielsen, Per Mose, Qi, Haiyun, Ringgaard, Steffen, and Laustsen, Christoffer

Subjects
urogenital system, Journal Article
Abstract

PURPOSE: To investigate the correlation between renal ischemia and 13 C-urea T2 relaxation rate in an acute kidney injury (AKI) rat model.METHODS: Six rats subjected to unilateral renal ischemia were investigated. Creatinine clearance, urine output, plasma creatinine as well as blood-urea nitrogen (BUN) values were acquired before and after the procedure. 1 H T2* mapping was acquired using blood oxygenation level dependent (BOLD) MRI and hyperpolarized 13 C-urea T2 mapping was acquired using a 2D golden-angle radial approach. Kidney perfusion was estimated using noncontrast flow alternating inversion recovery arterial spin labeling.RESULTS: All rats showed clinical signs of AKI with increased plasma creatinine and increased BUN. Whole kidney 13 C-urea T2 significantly decreased 26% (P = 0.001) 24 h after reperfusion. A significantly different (3.7 times steeper; P = 0.008) osmolality gradient was observed in the contralateral kidney (P = 0.008; R2 = 0.86) compared with the postischemic kidney (P = 0.0004, R2 =0.97). Whole kidney T2* signal (P = 0.14) and T2* gradient (P = 0.26) was similar between the two kidneys. Oxygen availability dependency on 13 C-urea T2 was investigated by means of the correlation between the BOLD and T2 signals; a statistically significant difference (P = 0.03) was found in the contralateral kidney (P = 0.0001; R2 = 0.95), but not in the postischemic kidney (P = 0.31; R2 = 0.25).CONCLUSION: We demonstrate that hyperpolarized [13 C,15 N2 ]urea T2 relaxation correlates with renal oxygen tension ( T2*) in the healthy contralateral kidney, but not in the postischemic kidney. The whole kidney T2 relaxation difference between the postischemic and contralateral kidney may originate from altered blood volume in the postischemic kidney. Magn Reson Med, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

Published
2018

24. Acute renal metabolic effect of metformin treatment assessed with hyperpolarized magnetic resonance imaging

Author

Qi, Haiyun, Nielsen, Per Mose, Schroeder, Marie, Bertelsen, Lotte Bonde, Palm, Fredrik, and Laustsen, Christoffer

Subjects
endocrine system diseases
Abstract

Metformin is the primary anti-diabetic drug in type-2 diabetes patients. However, controversy exists on its use in patients with renal impairment. Here we investigated the acute metabolic effects of metformin treatment in rat kidneys, with hyperpolarized 13C pyruvate and Clark-electrodes. A significantly altered metabolic phenotype was observed 30 min post metformin treatment. Anaerobic metabolism was elevated in the cytosol, indicated by increased lactate/pyruvate ratio, and mitochondrial aerobic metabolism was reduced, indicated by decreased bicarbonate/pyruvate ratio. Acute metformin treatment increased renal blood flow with higher O2 saturation and did not change tubular O2 consumption. These results indicate that metformin reduces mitochondrial respiration and enhances anaerobic metabolism, even with enough oxygen supply, within only 30 min of treatment.

Published
2017

25. Detection of acute kidney injury with hyperpolarized [13C, 15N]Urea and multiexponential relaxation modeling.

Author

Grist, James T., Mariager, Christian Østergaard, Qi, Haiyun, Nielsen, Per Mose, and Laustsen, Christoffer

Subjects
ACUTE kidney failure, KIDNEY injuries, UREA, RELAXATION for health, REPERFUSION injury
Abstract

Purpose: To assess the utility of Laplacian fitting to describe the differences in hyperpolarized [13C, 15N]urea T2 relaxation in ischemic and healthy rodent kidneys. Methods: Six rats with unilateral renal ischemia were investigated. [13C, 15N]Urea T2 mapping was undertaken with a radial fast spin echo method, with subsequent postprocessing performed with regularized Laplacian fitting. Results: Simulations showed that Laplacian fitting was stable down to a signal‐to‐noise ratio of 20. In vivo results showed a significant increase in the mono‐ and decrease in biexponential pools in ischemia reperfusion injury kidneys, in comparison to healthy (14 ± 10% versus 4 ± 2%, 85 ± 10% versus 95 ± 3%; P <.05). Conclusion: We demonstrate, for the first time, the differences in multiexponential behavior of [13C, 15N]urea between the healthy and ischemic rodent kidney. The distribution of relaxation pools were found to be both visually and numerically significantly different. The ability to improve the information level in hyperpolarized MR, by using the relaxation contrast mechanisms is an appealing option, that can easily be adopted in large animals and even in clinical studies in the near future. [ABSTRACT FROM AUTHOR]

Published
2020
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27. Effects of Unfiltered Coffee and Bioactive Coffee Compounds on the Development of Metabolic Syndrome Components in a High-Fat-/High-Fructose-Fed Rat Model

Author

Shokouh, Pedram, primary, Jeppesen, Per, additional, Hermansen, Kjeld, additional, Laustsen, Christoffer, additional, Stødkilde-Jørgensen, Hans, additional, Hamilton-Dutoit, Stephen, additional, Søndergaard Schmedes, Mette, additional, Qi, Haiyun, additional, Stokholm Nørlinger, Thomas, additional, and Gregersen, Søren, additional

Published
2018
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29. Effects of Unfiltered Coffee and Bioactive Coffee Compounds on the Development of Metabolic Syndrome Components in a High‐Fat/High‐Fructose-Fed Rat Model

Author

Shokouh, Pedram, primary, Jeppesen, Per Bendix, additional, Hermansen, Kjeld, additional, Laustsen, Christoffer, additional, Stødkilde-Jørgensen, Hans, additional, Hamilton-Dutoit, Stephen Jacques, additional, Søndergaard Schmedes, Mette, additional, Qi, Haiyun, additional, Stokholm Nørlinger, Thomas, additional, and Gregersen, Soeren, additional

Published
2018
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35. Antioxidant treatment attenuates lactate production in diabetic nephropathy

Author

Laustsen, Christoffer, Nielsen, Per Mose, Nørlinger, Thomas Stokholm, Qi, Haiyun, Pedersen, Uffe Kjærgaard, Bertelsen, Lotte Bonde, Østergaard, Jakob Appel, Flyvbjerg, Allan, Ardenkjær-Larsen, Jan Henrik, Palm, Fredrik, Stødkilde-Jørgensen, Hans, Laustsen, Christoffer, Nielsen, Per Mose, Nørlinger, Thomas Stokholm, Qi, Haiyun, Pedersen, Uffe Kjærgaard, Bertelsen, Lotte Bonde, Østergaard, Jakob Appel, Flyvbjerg, Allan, Ardenkjær-Larsen, Jan Henrik, Palm, Fredrik, and Stødkilde-Jørgensen, Hans

Abstract

The early progression of diabetic nephropathy is notoriously difficult to detect and quantify before the occurrence of substantial histological damage. Recently, hyperpolarized [1-(13)C]pyruvate has demonstrated increased lactate production in the kidney early after the onset of diabetes, implying increased lactate dehydrogenase activity as a consequence of increased nicotinamide adenine dinucleotide substrate availability due to upregulation of the polyol pathway, i.e., pseudohypoxia. In this study, we investigated the role of oxidative stress in mediating these metabolic alterations using state-of-the-art hyperpolarized magnetic resonance (MR) imaging. Ten-week-old female Wistar rats were randomly divided into three groups: healthy controls, untreated diabetic (streptozotocin treatment to induce insulinopenic diabetes), and diabetic, receiving chronic antioxidant treatment with TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl) via the drinking water. Examinations were performed 2, 3, and 4 wk after the induction of diabetes by using a 3T Clinical MR system equipped with a dual tuned (13)C/(1)H-volume rat coil. The rats received intravenous hyperpolarized [1-(13)C]pyruvate and were imaged using a slice-selective (13)C-IDEAL spiral sequence. Untreated diabetic rats showed increased renal lactate production compared with that shown by the controls. However, chronic TEMPOL treatment significantly attenuated diabetes-induced lactate production. No significant effects of diabetes or TEMPOL were observed on [(13)C]alanine levels, indicating an intact glucose-alanine cycle, or [(13)C]bicarbonate, indicating normal flux through the Krebs cycle. In conclusion, this study demonstrates that diabetes-induced pseudohypoxia, as indicated by an increased lactate-to-pyruvate ratio, is significantly attenuated by antioxidant treatment. This demonstrates a pivotal role of oxidative stress in renal metabolic alterations occurring in early diabetes.

Published
2017
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36. Diabetes induced renal urea transport alterations assessed with 3D hyperpolarized (13) C,(15) N-Urea

Author

Bertelsen, Lotte B, Nielsen, Per M, Qi, Haiyun, Nørlinger, Thomas S, Zhang, Xiaolu, Stødkilde-Jørgensen, Hans, and Laustsen, Christoffer

Abstract

PURPOSE: In the current study, we investigated hyperpolarized urea as a possible imaging biomarker of the renal function by means of the intrarenal osmolality gradient.METHODS: Hyperpolarized three-dimensional balanced steady state (13) C MRI experiments alongside kidney function parameters and quantitative polymerase chain reaction measurements was performed on two groups of rats, a streptozotocin type 1 diabetic group and a healthy control group.RESULTS: A significant decline in intrarenal steepness of the urea gradient was found after 4 weeks of untreated insulinopenic diabetes in agreement with an increased urea transport transcription.CONCLUSION: MRI and hyperpolarized [(13) C,(15) N]urea can monitor the changes in the corticomedullary urea concentration gradients in diabetic and healthy control rats. Magn Reson Med, 2016. © 2016 Wiley Periodicals, Inc.

Published
2016

41. The chinchilla as a novel animal model of pregnancy

Author

Mikkelsen, Emmeli, primary, Lauridsen, Henrik, additional, Nielsen, Per Mose, additional, Qi, Haiyun, additional, Nørlinger, Thomas, additional, Andersen, Maria Dahl, additional, Uldbjerg, Niels, additional, Laustsen, Christoffer, additional, Sandager, Puk, additional, and Pedersen, Michael, additional

Published
2017
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43. Hyperbaric oxygen therapy reduces renal lactate production

Author

Nørlinger, Thomas S., primary, Nielsen, Per Mose, additional, Qi, Haiyun, additional, Mikkelsen, Emmeli, additional, Hansen, Kasper, additional, Schmidt, Nikolaj H., additional, Pedersen, Michael, additional, Agger, Peter, additional, Palm, Fredrik, additional, and Laustsen, Christoffer, additional

Published
2017
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44. Antioxidant treatment attenuates lactate production in diabetic nephropathy

Author

Laustsen, Christoffer, primary, Nielsen, Per Mose, additional, Nørlinger, Thomas Stokholm, additional, Qi, Haiyun, additional, Pedersen, Uffe Kjærgaard, additional, Bertelsen, Lotte Bonde, additional, Østergaard, Jakob Appel, additional, Flyvbjerg, Allan, additional, Ardenkjær-Larsen, Jan Henrik, additional, Palm, Fredrik, additional, and Stødkilde-Jørgensen, Hans, additional

Published
2017
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45. Organ‐specific metabolic profiles of the liver and kidney during brain death and afterwards during normothermic machine perfusion of the kidney

Author

Erp, Anne C., Qi, Haiyun, Jespersen, Nichlas R., Hjortbak, Marie V., Ottens, Petra J., Wiersema‐Buist, Janneke, Nørregaard, Rikke, Pedersen, Michael, Laustsen, Christoffer, Leuvenink, Henri G. D., and Jespersen, Bente

Abstract

We investigated metabolic changes during brain death (BD) using hyperpolarized magnetic resonance (MR) spectroscopy and ex vivo graft glucose metabolism during normothermic isolated perfused kidney (IPK) machine perfusion. BD was induced in mechanically ventilated rats by inflation of an epidurally placed catheter; sham‐operated rats served as controls. Hyperpolarized [1‐13C]pyruvate MR spectroscopy was performed to quantify pyruvate metabolism in the liver and kidneys at 3 time points during BD, preceded by injecting hyperpolarized[1‐13C]pyruvate. Following BD, glucose oxidation was measured using tritium‐labeled glucose (d‐6‐3H‐glucose) during IPK reperfusion. Quantitative polymerase chain reaction and biochemistry were performed on tissue/plasma. Immediately following BD induction, lactate increased in both organs (liver: eµd0.21, 95% confidence interval [CI] [−0.27, −0.15]; kidney: eµd0.26, 95% CI [−0.40, −0.12]. After 4 hours of BD, alanine production decreased in the kidney (eµd0.14, 95% CI [0.03, 0.25], P< .05). Hepatic lactate and alanine profiles were significantly different throughout the experiment between groups (P< .01). During IPK perfusion, renal glucose oxidation was reduced following BD vs sham animals (eµd0.012, 95% CI [0.004, 0.03], P< .001). No differences in enzyme activities were found. Renal gene expression of lactate‐transporter MCT4 increased following BD (P< .01). In conclusion, metabolic processes during BD can be visualized in vivo using hyperpolarized magnetic resonance imaging and with glucose oxidation during ex vivo renal machine perfusion. These techniques can detect differences in the metabolic profiles of the liver and kidney following BD. Differences in glucose metabolism in the liver and kidney can be visualized in vivo during brain death using hyperpolarized magnetic resonance spectroscopy and ex vivo following brain death during normothermic kidney machine perfusion using glucose oxidation.

Published
2020
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46. Assessment of mouse liver [1-13C]pyruvate metabolism by dynamic hyperpolarized MRS.

Author

Faarkrog Høyer, Kasper, Laustsen, Christoffer, Ringgaard, Steffen, Qi, Haiyun, Østergaard Mariager, Christian, Svava Nielsen, Thomas, Kraemer Sundekilde, Ulrik, Treebak, Jonas T, Jessen, Niels, and Stødkilde-Jørgensen, Hans

Subjects
FATTY liver, METABOLISM, LIVER, NUCLEAR magnetic resonance spectroscopy, PYRUVATES, BLOOD sugar
Abstract

Hyperpolarized [1-13C]pyruvate magnetic resonance (MR) spectroscopy has the unique ability to detect real-time metabolic changes in vivo owing to its high sensitivity compared with thermal MR and high specificity compared with othe r metabolic imaging methods. The aim of this study was to explore the potential of hyperpolarized MR spectroscopy for quantification of liver pyruvate metabolism dur ing a hyperinsulinemic- isoglycemic clamp in mice. Hyperpolarized [1-13C]pyruvate was used for in vivo MR spectroscopy of liver pyruvate metabolism in mice. Mice were divided into two groups: (i) non-stimulated 5-h fasted mice and (ii) hyperinsulinemic-isoglycemic clamped mice. During clamp conditions, insulin and donor blood were administered at a constant rate, whereas glucose was infused to maintain isoglycemia. When steady state was reached, insulin-stimulated mice were rapidly infused with hyperpolarized [1-13C]pyruvate for real-time tracking of the dynamic distribution of metabolic derivatives from pyruvate, such as [1-13C]lactate, [1-13C]alanine and [13C]bicarbonate. Isotopomer analysis of plasma glucose confirmed 13C-incorporation from [1-13C]pyruvate into glucose was increased in fasted mice compared with insulin-stimulated mice, demonstrating an increased gluconeogenesis in fasted mice. The AUC ratios for [1-13C]alanine/ [1-13C]pyruvate (38.2%), [1-13C]lactate/[1-13C]pyruvate (41.8%) and [13C]bicarbonate/ [1-13C]pyruvate (169%) all increased significantly during insulin sti mulation. Hyperpolarized [1-13C]pyruvate can be used for in vivo MR spectroscopy of liver pyruvate metabolism during hyperinsulinemic-isoglycemic clamp conditions. Under these conditions, insulin decreased gluconeogenesis and increased [1-13C]alanine, [1-13C]lactate and [13C]bicarbonate after a [1-13C]pyruvate bolus. This application of in vivo spectroscopy has the potential to identify impairments in spec ific metabolic pathways in the liver associated with obesity, insulin resistance and nonalcoholic fatty liver disease. [ABSTRACT FROM AUTHOR]

Published
2019
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