On the reliability of ¹³C metabolic modeling with two-compartment neuronal-glial models

Metabolic modeling of ¹³C NMR spectroscopy (¹³C MRS) data using two-compartment neuronal-glial models enabled non-invasive measurements of the glutamate-glutamine cycle rate (V_NT) in the brain in vivo. However, the reliability of such two-compartment metabolic modeling has not been examined thoroughly. This study uses Monte-Carlo simulations to investigate the reliability of metabolic modeling of ¹³C positional enrichment time courses measured in brain amino acids such as glutamate and glutamine during [1-¹³C]- or [1,6-¹³C₂]glucose infusion. Results show that the determination of V_NT is not very precise under experimental conditions typical of in vivo NMR studies, whereas the neuronal TCA cycle rate V_TCA(N) is determined with a much higher precision. Consistent with these results, simulated ¹³C positional enrichment curves for glutamate and glutamine are much more sensitive to the value of V_TCA(N) than to the value of V_NT. We conclude that the determination of the glutamate-glutamine cycle rate V_NT using ¹³C MRS is relatively unreliable when fitting ¹³C positional enrichment curves obtained during [1-¹³C] or [1,6- ¹³C₂]glucose infusion. Further developments are needed to improve the determination of V_NT , for example using additional information from ¹³C-¹³C isotopomers and/or using glial specific substrates such as [2-¹³C]acetate.