Quantification of hepatic transaldolase exchange activity and its effects on tracer measurements of indirect pathway flux in humans

Jones, John G.; Garcia, Paula; Barosa, Cristina; Delgado, Teresa C.; Caldeira, M.Madalena; Diogo, Luísa

doi:10.1002/mrm.21451

Cited by 12 publications

(17 citation statements)

References 21 publications

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“…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.…”

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confidence: 99%

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

Jin

Sherry

Malloy

2014

Journal of Biological Chemistry

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Background: Hepatic pentose phosphate pathway activity is difficult to monitor in vivo. Results: Hepatic pentose phosphate pathway results in different ratios of doubly labeled glucose isotopomers after administration of [U-13 C 3 ]glycerol. Conclusion: [1,2-13 C 2 ]glucose produced by the hepatic pentose phosphate pathway is quantified. Significance: A simple method is presented to detect the activity of hepatic pentose phosphate pathway in vivo from analysis of plasma glucose.

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

Jin

Sherry

Malloy

2014

Journal of Biological Chemistry

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“…As described recently, the effects of TA on measurements of gluconeogenesis by the 2 H 2 O method can be corrected by analyzing 13 C3/ 13 C4 from coadministration of a 13 C tracer (3,12,21). Since equilibration of the 13 C label between glyceraldehyde 3-phosphate and dihydroxyacetone phosphate (DHAP) via TPI is essentially complete, the 13 C tracer can be a DHAP precursor (i.e., [ 13 C]glycerol or dihydroxyacetone) or a glyceraldehyde 3-phosphate precursor ( 13 C-propionate, acetate, or bicarbonate), although glucose enrichment from the latter group is less sensitive to incomplete TPI exchange (21).…”

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confidence: 99%

“…Excess 13 C enrichment was calculated as the ratio of doublet to singlet multiplied by 1.11% (21). The 13 C NMR analyses were performed with a BrukerAvance III 600 system equipped with a 5-mm TCP-QNP cold probe.…”

Section: Methodsmentioning

confidence: 99%

“…gluconeogenesis; deuterated water; transaldolase; triose phosphate isomerase AFTER AN OVERNIGHT FAST, plasma glucose is not symmetrically labeled from gluconeogenic carbon tracers such as [U- 13 C] glycerol (21) and [3-14 C]lactate (25). Exchange of fructose 6-phosphate and triose phosphate mediated by transaldolase has been implicated by us (3,7,9) and others (12) in overestimation of rates of gluconeogenesis, utilizing the deuterated water method.…”

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confidence: 99%

“…1). When the carbon label is derived from glycerol instead of acetate, incomplete TPI exchange results in the opposite glucose C3/C4 labeling asymmetry (i.e., 13 C3/ 13 C4 Ͼ 1.0), whereas TA activity promotes a higher enrichment of glucose carbon 4 relative to carbon 3 for both tracers (21). Thus, by comparing glucose 13 C3/ 13 C4 from both acetate and glycerol, the contributions of incomplete TPI exchange and TA activity to the glucose-labeling asymmetry can be resolved.…”

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confidence: 99%

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Effects of transaldolase exchange on estimates of gluconeogenesis in type 2 diabetes

Rajpal

Dube

Carvalho

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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13 C]acetate during a separate visit in a subset of ND (n ϭ 7) subjects. Ratio of 13 C3/ 13 C4 obtained following either tracer was Ͻ1.0 at baseline and during clamp, indicating that TPI exchange was essentially complete and did not contribute to asymmetric glucose enrichment. Uncorrected and corrected rates of gluconeogenesis were no different (P ϭ not significant) in T2DM vs. ND both at baseline and during clamp. TA correction resulted in equivalent estimates of corrected gluconeogenesis in T2DM and ND that were ϳ25-35% lower than uncorrected gluconeogenesis both at baseline and during the clamp. The asymmetric enrichment of glucose from 13 C-gluconeogenic tracers is attributable to TA exchange and can be utilized to correct for TA exchange. In conclusion, TA exchange does not differ between T2DM and ND under fasting or hyperglycemic clamp conditions, and the 2 H2O method continues to provide an accurate estimation of gluconeogenesis. gluconeogenesis; deuterated water; transaldolase; triose phosphate isomerase AFTER AN OVERNIGHT FAST, plasma glucose is not symmetrically labeled from gluconeogenic carbon tracers such as [U-13 C] glycerol (21) and [3-14 C]lactate (25). Exchange of fructose 6-phosphate and triose phosphate mediated by transaldolase has been implicated by us (3, 7, 9) and others (12) in overestimation of rates of gluconeogenesis, utilizing the deuterated water method. In this method, glucose derived from glycogenolysis (GGL) via glucose 6-phosphate (G6P) source can become labeled in carbons 4, 5, and 6 from either a carbonlabeled gluconeogenic precursor or deuterated water independent of gluconeogenesis. This results in an overestimation of the gluconeogenic fraction and a corresponding underestimation of the glycogenolytic contribution to endogenous glucose production. This exchange is particularly important in the study of type 2 diabetes mellitus (T2DM) since it mimics the characteristic shift toward increased hepatic gluconeogenic activity during the progression of this disease. With a few exceptions (14), stable isotope tracer studies indicate an increased fractional gluconeogenesis in overnight-fasted T2DM subjects compared with healthy nondiabetic (ND) controls (6,10,15,16,28). Transaldolase (TA) exchange activity has been implicated in both ND and T2DM subjects from the depletion of position 5 relative to position 3 label following metabolism of [3, H 2 ]galactose to glucose (7). However, it is not known whether transaldolase exchange activity is different between ND and T2DM under conditions of fasting and hyperglycemia (frequently seen with meals). This study was undertaken to compare TA exchange reaction in ND and T2DM subjects using [1-13 C]acetate infusion under conditions of fasting and during a hyperglycemic moderate-dose insulin clamp to determine whether or not TA exchange activity explains differences in glucose enrichment from gluconeogenic substrates between ND and T2DM subjects.We have demonstrated that TA activity occurs in healthy humans based on a higher enrichment of gluco...

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

Delgado

Silva

Fernandes

et al. 2009

Magnetic Resonance in Med

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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-(13)C]glucose and 3.33% [U-(2)H(7)]glucose and analysis of plasma glucose and hepatic uridine diphosphate-glucose enrichments (sampled as urinary menthol glucuronide) by (2)H and (13)C nuclear magnetic resonance. The direct pathway contribution, as estimated from the dilution of [U-(13)C]glucose between plasma glucose and glucuronide, was unexpectedly low (36 +/- 5%). With [U-(2)H(7)]glucose, direct pathway estimates based on the dilution of position 3 (2)H-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, (2)H-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.

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Quantification of hepatic transaldolase exchange activity and its effects on tracer measurements of indirect pathway flux in humans

Cited by 12 publications

References 21 publications

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

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

Effects of transaldolase exchange on estimates of gluconeogenesis in type 2 diabetes

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

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