Evidence That Processes Other Than Gluconeogenesis May Influence the Ratio of Deuterium on the Fifth and Third Carbons of Glucose

Abstract

OBJECTIVE-The deuterated water method uses the ratio of deuterium on carbons 5 and 2 (C5/C2) or 3 and 2 (C3/C2) to estimate the fraction of glucose derived from gluconeogenesis. The current studies determined whether C3 and C5 glucose enrichment is influenced by processes other than gluconeogenesis.RESEARCH DESIGN AND METHODS-Six nondiabetic subjects were infused with [3,5-2 H 2 ]glucose and insulin while glucose was clamped at ϳ5 mmol/l; the C5-to-C3 ratio was measured in the in UDP-glucose pool using nuclear magnetic resonance and the acetaminophen glucuronide method.RESULTS-Whereas the C5-to-C3 ratio of the infusate was 1.07, the ratio in UDP-glucose was Ͻ1.0 in all subjects both before (0.75 Ϯ 0.07) and during (0.67 Ϯ 0.05) the insulin infusion.CONCLUSIONS-These data indicate that the deuterium on C5 of glucose is lost more rapidly relative to the deuterium on C3. The decrease in the C5-to-C3 ratio could result from exchange of the lower three carbons of fructose-6-phosphate with unlabeled three-carbon precursors via the transaldolase reaction and/or selective retention of the C3 deuterium at the level of triosephosphate isomerase due to a kinetic isotope effect. After ingestion of 2 H 2 O, these processes would increase the enrichment of C5 and decrease the enrichment of C3, respectively, with the former causing an overestimation of gluconeogenesis using the C2-to-C5 ratio and the latter an underestimation using the C3-to-C2 ratio. Future studies will be required to determine whether the impact of these processes on the measurement of gluconeogenesis differs among the disease states being evaluated (e.g., diabetes or obesity). Diabetes 57:50-55, 2008

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“…Therefore, whenever a triose molecule is converted to glucose, enrichment at either C5 or C3 can be used to measure GNG. However, enrichment of C5 and also of C3 can be influenced by other processes than GNG such as the transaldolase reaction which will result in an overestimate of GNG (Bock et al 2008). On the contrary, exchange of the C3 hydrogen with deuterium during the triosephosphate isomerase reaction may result in a lower than expected enrichment in C3 and therefore an underestimate of GNG.…”

“…On the contrary, exchange of the C3 hydrogen with deuterium during the triosephosphate isomerase reaction may result in a lower than expected enrichment in C3 and therefore an underestimate of GNG. Bock et al (2008) showed that the deuterium on C5 of glucose is lost more rapidly relative to the deuterium on C3. This may result in an overestimation of GNG using the C5 ⁄ C2 ratio and an underestimation using the C3 ⁄ C2 ratio.…”

“…Therefore, the plasma C5 ⁄ C2 glucose ratio is used to estimate the fraction of glucose derived from GNG. As the third carbon of glucose (C3) and C5 are concurrently labelled during the triose isomerase reaction, the C3 ⁄ C2 ratio also has been used to assess GNG (Jones et al 2000;Bock et al 2008).…”

Interaction between the Pentose Phosphate Pathway and Gluconeogenesis from Glycerol in the Liver

“…1A). After exposure to [U- 13 C 3 ]glycerol, the liver produces primarily [1,2,[3][4][5][6][7][8][9][10][11][12][13] C 3 ]glucose and [4,5,[6][7][8][9][10][11][12][13] C 3 ]glucose after equilibration of DHAP and GA3P through TPI. [U- 13 C 6 ]glucose is also produced, but it will not be considered further for simplicity because it is trivial in the current study.…”

“…The three-carbon unit can then condense with glyceraldehyde 3-phosphate (GA3P) to yield fructose 6-phosphate (F6P) and erythrose 4-phosphate. The transaldolase reaction also directly exchanges carbons 4 -6 of F6P with GA3P (12)(13)(14)(15)(16)(17). The fourth relevant pathway involves possible redistribution of carbon tracers in the oxidative arm of the PPP.…”