Glycerol's contribution to lactate production outside of a glucose intermediate in fasting humans

Background: Glycerol is a well-recognized substrate for new glucose production via gluconeogenesis in the liver. However, its carbon contribution to the glycolytic intermediate lactate is not known in humans.

Methods: Here we infused stable isotope tracers ¹³C₃-glycerol and 6,6-D₂-glucose into six metabolically healthy individuals after an overnight fast to study glycerol metabolism and measure glucose rate of appearance. Serum samples underwent liquid chromatography-mass spectrometry analysis.

Results: Glycerol and glucose rates of appearance were 2.21 ± 1.42 μmol/kg/min and 7.81 ± 1.15 μmol/kg/min, respectively. Under steady-state conditions, the ¹³C enrichment for lactate was significantly higher than that of glucose (2.90 ± 0.52% versus 1.53 ± 0.78%, p = 0.017), suggesting direct glycerol to lactate metabolism. The percentage of lactate derived from glycerol was also significantly higher than the percentage of glucose (13.88 ± 2.69% versus 6.50 ± 2.59%, p = 0.005).

Conclusion: Given that lactate itself is a carbon source for gluconeogenesis and tricycarboxylic cycle intermediates, glycerol's ability to donate carbons to lactate may make it quantitatively more important to intermediary metabolism than currently appreciated.