Role of glucose and glutamine synthesis in the differential recovery of ¹³CO₂ from infused [2-¹³C] versus [1-¹³C] acetate☆

Abstract 

Carbon exchange in the Krebs cycle may result in underestimation of substrate oxidation measured with ¹³C-labeled substrates, since carbon labeled in position 2 of acetyl-coenzyme A (CoA) could be incorporated into glucose (via gluconeogenesis) and glutamine. Five healthy volunteers were therefore infused with [1-¹³C] and [2-¹³C] acetate at a rate of 0.5 μmol · kg⁻¹ · min⁻¹ for 165 minutes on two different occasions in randomized order. Whole body acetate turnover did not differ between the two tracers: 7.9 ± 0.3 and 7.5 ± 0.6 μmol · kg⁻¹ · min⁻¹ (nonsignificant [NS]) for [1-¹³C] and [2-¹³C] acetate, respectively. Isotopic ¹³C enrichment was higher in expired CO₂ (0.177 ± 0.021 v 0.089 ± 0.009 atom percent excess [APE], P < .01) and lower in glucose (0.074 ± 0.017 v 0.291 ± 0.061 mole percent excess [MPE], P < .01) for [1-¹³C] acetate compared with [2-¹³C] acetate, respectively, at the end of the infusions. Glutamine isotopic enrichment was slightly but not significantly higher when infusing [1-¹³C] acetate versus [2-¹³C] acetate (0.348 ± 0.038 v 0.495 ± 0.069 MPE, NS, respectively). At the end of the experiment, the recovery of ¹³CO₂ from [1-¹³C] acetate was 44.8% ± 2.7%, and from [2-¹³C] acetate, 22.6% ± 1.3%. A significant correlation was observed between the differences in ¹³C enrichment of CO₂ for the two tracers and glucose (ΔCO₂ = 0.424 · Δglucose + 0.001, R² = .9856, P = .0007) or glutamine (ΔCO₂ = 0.621 · Δglutamine + 0.004, R² = .9573, P = .0038) during the infusion. These results suggest that (1) although gluconeogenesis appears to be more responsible than glutamine for the differential recovery of [2-¹³C] versus [1-¹³C] acetate, other secondary pathways are probably also implicated; and (2) different recovery correction factors should be applied when measuring substrate oxidation with a stable isotope tracer depending on the expected position of ¹³C in acetyl-CoA.

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