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

Implications for the Use of ²H₂O to Measure Gluconeogenesis in Humans

Gerlies Bock¹, William C. Schumann², Rita Basu¹, Shawn C. Burgess³, Zheng Yan³, Visvanathan Chandramouli², Robert A. Rizza¹, and Bernard R. Landau^2,

¹ Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota
² The Advanced Imaging Research Center, Case Western Reserve University School of Medicine, Cleveland, Ohio
³ the University of Texas Southwestern Medical Center, Dallas, Texas

Address correspondence and reprint requests to Robert A. Rizza, MD, Mayo Clinic, 200 1st St. SW, Rm. 5-194 Joseph, Rochester, MN 55905. E-mail: rizza.robert{at}mayo.edu

Key Words: DHAP, dihydroxyacetone phosphate • G3P, glyceraldhyde-3 phosphate • MAG, monoacetoneglucose • NMR, nuclear magnetic resonance • THF, tetrahydrofuran

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 [3,5-²H₂]glucose and insulin while glucose was clamped at 5 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 <1.0 in all subjects both before (0.75 ± 0.07) and during (0.67 ± 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 ²H₂O, 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).

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