Measuring the glutamate‐glutamine cycle rate in the brain: simulated comparison between [1‐ 13 C]glucose and [2‐ 13 C]acetate

13 C NMR together with metabolic modeling has allowed non‐invasive measurements of the glutamate‐glutamine cycle rate (V NT ) between neurons and astrocytes [1]. However, the determination of the V NT flux is not very precise when using [1‐ 13 C] or [1,6‐ 13 C 2 ]glucose as a substrate [2]. The goal of this work was to use simulations and experimental data to determine whether dynamic metabolic modeling using a glial‐specific substrate (such as [2‐ 13 C]acetate) leads to improved precision on V NT . Simulated 13 C turnover curves for glutamate and glutamine were found to be more sensitive to the value of V NT when using [2‐ 13 C]acetate than when using [1‐ 13 C]glucose as a substrate (Figure 1). When infusing [1‐ 13 C]glucose, the turnover curves for glutamate and glutamine C4 remained almost unchanged when V NT was varied by ±50%. In contrast, with [2‐ 13 C]acetate, the turnover curves for both glutamate and glutamine C4 changed noticeably. This suggests that the determination of V NT would be more reliable when infusing [2‐ 13 C]acetate compared to [1‐ 13 ]glucose. Monte‐Carlo simulations confirmed that V NT is indeed much more precise when using [2‐ 13 C]acetate: the standard deviation on V NT was 670 % for [1‐ 13 C]glucose and only 12% for [2‐ 13 C]acetate. We conclude that dynamic metabolic modeling using [2‐ 13 C]acetate as a substrate has the potential to improve the determination of the glutamate‐glutamine cycle rate V NT compared to using [1‐ 13 C] or [1,6‐ 13 C 2 ] glucose. This work was supported by NIH R01NS38672 and P41RR08079. 1Sensitivity of glutamate and glutamine 13 C turnover curves to the value of the glutamate‐glutamine cycle rate V NT when using (a) [1‐ 13 C]glucose and (b) [2‐ 13 C]acetate. Turnover curves were more sensitive to the value of V NT with [2‐ 13 C]acetate than with [1‐ 13 C]glucose.2Probability distribution of V NT determined by Monte‐Carlo simulations. Estimation of V NT was more precise with [2‐ 13 C]acetate than with [1‐ 13 C]glucose.