Sources of hepatic glycogen synthesis during an oral glucose tolerance test: Effect of transaldolase exchange on flux estimates

Sources of hepatic glycogen synthesis during an oral glucose tolerance test were evaluated in six healthy subjects by enrichment of a 75-g glucose load with 6.67% [U-13C]glucose and 3.33% [U-2H7]glucose and analysis of plasma glucose and hepatic uridine diphosphate–glucose enrichments (sampled as urinary menthol glucuronide) by 2H and 13C nuclear magnetic resonance. The direct pathway contribution, as estimated from the dilution of [U-13C]glucose between plasma glucose and glucuronide, was unexpectedly low (36 ± 5%). With [U-2H7]glucose, direct pathway estimates based on the dilution of position 3 2H-enrichment between plasma glucose and glucuronide were significantly higher (51 ± 6%, P = 0.05). These differences reflect the exchange of the carbon 4, 5, and 6 moiety of fructose-6-phosphate and glyceraldehyde-3-phosphate catalyzed by transaldolase. As further evidence of this exchange, 2H-enrichments in glucuronide positions 4 and 5 were inferior to those of position 3. From the difference in glucuronide positions 5 and 3 enrichments, the fraction of direct pathway carbons that experienced transaldolase exchange was estimated at 21 ± 4%. In conclusion, the direct pathway contributes only half of hepatic glycogen synthesis during an oral glucose tolerance test. Glucose tracers labeled in positions 4, 5, or 6 will give significant underestimates of direct pathway activity because of transaldolase exchange. Magn Reson Med, 2009. © 2009 Wiley-Liss, Inc.