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A new hyperpolarized 13C ketone body probe reveals an increase in acetoacetate utilization in the diabetic rat heart.

ABSTRACT: Emerging studies have recently shown the potential importance of ketone bodies in cardio-metabolic health. However, techniques to determine myocardial ketone body utilization in vivo are lacking. In this work, we developed a novel method to assess myocardial ketone body utilization in vivo using hyperpolarized [3-13C]acetoacetate and investigated the alterations in myocardial ketone body metabolism in diabetic rats. Within a minute upon injection of [3-13C]acetoacetate, the production of [5-13C]glutamate and [1-13C] acetylcarnitine can be observed real time in vivo. In diabetic rats, the production of [5-13C]glutamate was elevated compared to controls, while [1-13C]acetylcarnitine was not different. This suggests an increase in ketone body utilization in the diabetic heart, with the produced acetyl-CoA channelled into the tricarboxylic acid cycle. This observation was corroborated by an increase activity of succinyl-CoA:3-ketoacid-CoA transferase (SCOT) activity, the rate-limiting enzyme of ketone body utilization, in the diabetic heart. The increased ketone body oxidation in the diabetic hearts correlated with cardiac hypertrophy and dysfunction, suggesting a potential coupling between ketone body metabolism and cardiac function. Hyperpolarized [3-13C]acetoacetate is a new probe with potential for non-invasive and real time monitoring of myocardial ketone body oxidation in vivo, which offers a powerful tool to follow disease progression or therapeutic interventions.

SUBMITTER: Abdurrachim D

PROVIDER: S-EPMC6445118 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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A new hyperpolarized 13C ketone body probe reveals an increase in acetoacetate utilization in the diabetic rat heart.

Abdurrachim Desiree D Woo Chern Chiuh CC Teo Xing Qi XQ Chan Wei Xin WX Radda George K GK Lee Philip Teck Hock PTH

Scientific reports 20190402 1

Emerging studies have recently shown the potential importance of ketone bodies in cardio-metabolic health. However, techniques to determine myocardial ketone body utilization in vivo are lacking. In this work, we developed a novel method to assess myocardial ketone body utilization in vivo using hyperpolarized [3-13C]acetoacetate and investigated the alterations in myocardial ketone body metabolism in diabetic rats. Within a minute upon injection of [3-13C]acetoacetate, the ...[more]

PMID: 30940842

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Project description:RationaleThe recent development of hyperpolarized 13C magnetic resonance spectroscopy has made it possible to measure cellular metabolism in vivo, in real time.ObjectiveBy comparing participants with and without type 2 diabetes mellitus (T2DM), we report the first case-control study to use this technique to record changes in cardiac metabolism in the healthy and diseased human heart.Methods and resultsThirteen people with T2DM (glycated hemoglobin, 6.9±1.0%) and 12 age-matched healthy controls underwent assessment of cardiac systolic and diastolic function, myocardial energetics (31P-magnetic resonance spectroscopy), and lipid content (1H-magnetic resonance spectroscopy) in the fasted state. In a subset (5 T2DM, 5 control), hyperpolarized [1-13C]pyruvate magnetic resonance spectra were also acquired and in 5 of these participants (3 T2DM, 2 controls), this was successfully repeated 45 minutes after a 75 g oral glucose challenge. Downstream metabolism of [1-13C]pyruvate via PDH (pyruvate dehydrogenase, [13C]bicarbonate), lactate dehydrogenase ([1-13C]lactate), and alanine transaminase ([1-13C]alanine) was assessed. Metabolic flux through cardiac PDH was significantly reduced in the people with T2DM (Fasted: 0.0084±0.0067 [Control] versus 0.0016±0.0014 [T2DM], Fed: 0.0184±0.0109 versus 0.0053±0.0041; P=0.013). In addition, a significant increase in metabolic flux through PDH was observed after the oral glucose challenge (P<0.001). As is characteristic of diabetes mellitus, impaired myocardial energetics, myocardial lipid content, and diastolic function were also demonstrated in the wider study cohort.ConclusionsThis work represents the first demonstration of the ability of hyperpolarized 13C magnetic resonance spectroscopy to noninvasively assess physiological and pathological changes in cardiac metabolism in the human heart. In doing so, we highlight the potential of the technique to detect and quantify metabolic alterations in the setting of cardiovascular disease.

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A new hyperpolarized 13C ketone body probe reveals an increase in acetoacetate utilization in the diabetic rat heart.

Publications

A new hyperpolarized <sup>13</sup>C ketone body probe reveals an increase in acetoacetate utilization in the diabetic rat heart.

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