Am J Physiol Endocrinol Metab 290: E1212-E1217, 2006.
First published January 10, 2006; doi:10.1152/ajpendo.00279.2005
0193-1849/06 $8.00
Measurement of gluconeogenesis by deuterated water: the effect of equilibration time and fasting period
Gideon Allick,1
Saskia N. van der Crabben,1
Mariette T. Ackermans,2
Erik Endert,2 and
Hans P. Sauerwein1
1Department of Endocrinology and Metabolism, and 2Department of Clinical Chemistry, Laboratory of Endocrinology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Submitted 21 June 2005
; accepted in final form 8 January 2006
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ABSTRACT
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Fasting gluconeogenesis (GNG) is often quantified using the 2H2O technique, which is based on plasma 2H2O enrichment and ensuing enrichment of plasma glucose at the C5 and C2 positions. Fractional (fr)GNG can be calculated using the ratio of C5 to C2 enrichment or the ratio of C5 to plasma 2H2O enrichment. For the latter, equilibration of 2H2O and C2 is required. The optimal equilibration period of 2H2O and C2 remains to be elucidated. In six healthy male subjects fasted for 18 h, we studied the effects of 3-, 5-, and 15-h 2H2O incubation periods on 1) the equilibration of plasma 2H2O and C2 glucose enrichment, 2) the measurement of frGNG, and 3) C5 labeling of hepatic glycogen after 1 mg of glucagon administration. After 3-h 2H2O incubation, plasma 2H2O and C2 were not equilibrated, frGNG C5/2H2O and C5/C2 were also different as was gluconeogenesis calculated with C5/2H2O and C5/C2. After 5- and 15-h 2H2O incubation, plasma 2H2O and C2 were equilibrated, and frGNG C5/2H2O and C5/C2 were similar, as was GNG calculated with C5/2H2O and C5/C2. After glucagon administration, no difference of C5 enrichment was found between 3, 5, and 15 h of 2H2O incubation. In conclusion, for reliable measurement of GNG in healthy subjects with C5/2H2O incubation periods longer than 3 h are required. After 5- and 15-h 2H2O incubation, GNG can be reliably measured with C5/2H2O. Gluconeogenetic labeling of glycogen did not affect the results after 3, 5, or 15 h of 2H2O incubation.
FASTING GLUCONEOGENESIS is often quantified using the 2H2O technique, which is based on the ingestion 2H2O and subsequent measurement of the enrichment of C5 in glucose and plasma 2H2O enrichment (8, 9). Glucose produced by gluconeogenesis after ingestion of 2H2O will be labeled with deuterium at the C5 position. Glucose molecules produced by gluconeogenesis and glycogenolysis will be labeled with deuterium at the C2 position. The ratio of C5 and C2 enrichment of glucose constitutes fractional gluconeogenesis. Alternatively, fractional gluconeogenesis can be calculated by the ratio of C5 enrichment of glucose and plasma 2H2O enrichment. A requirement for the latter method is the complete equilibration of plasma 2H2O enrichment with C2 enrichment of glucose (9). Analysis of plasma 2H2O enrichment has preference over the analysis of C2 enrichment of plasma glucose, for its analysis is considerably less complicated.
Chandramouli et al. (5) have shown that, after a 3-h 2H2O equilibration period, C2 and plasma 2H2O enrichment had essentially achieved equilibration. However, in a previous study by the same group, equilibration of C2 and plasma 2H2O enrichment was barely achieved 5 h after 2H2O ingestion (9). Studies by Chen et al. and Wajngot et al. have found that C2 label and plasma 2H2O enrichment are in steady state after, respectively, 9 and 11.75 h of equilibration (6, 11, 12). For reliable measurement of fractional gluconeogenesis using the fraction of C5 and plasma 2H2O enrichment, a long equilibration period seems to be required.
Besides the possible advantage of a long equilibration period, a disadvantage could be invoked. In the fasted state, glycogen cycling is thought to persist (7, 10). This could cause labeling of hepatic glycogen by incorporation of gluconeogenetically labeled glucose. Breakdown of this glycogen during measurement of fractional gluconeogenesis could result in an overestimation of gluconeogenesis at the expense of glycogenolysis. On the other hand, during short equilibration periods, glycogen cycling could underestimate gluconeogenesis if gluconeogenetically labeled glucose is incorporated into glycogen while unlabeled glucose is released from glycogen. Glycogen labeling during equilibration can be investigated by measuring C5 enrichment of glucose immediately after glucagon administration. As glucagon is a powerful stimulator of glycogenolysis, differences of C5 enrichment between short and long equilibration periods would indicate gluconeogenetic labeling of glycogen.
In many of the 2H2O studies performed by our and other groups, long equilibration periods (
15 h) were used to guarantee equilibration of plasma 2H2O and C2 glucose enrichment (2, 3). 2H2O ingestion a few hours before the study is preferable: possible labeling of glycogen is minimized and overnight admission of subjects is prevented. However, the shortest 2H2O equilibration period for reliable measurement of gluconeogenesis remains to be investigated.
To find the optimal 2H2O equilibration period, we studied the effects of 3-, 5-, and 15-h 2H2O incubation periods on 1) the equilibration of plasma 2H2O and C2 glucose enrichment, 2) the measurement of fractional gluconeogenesis using the ratio of C5 to 2H2O enrichment (C5/2H2O) and the ratio of C5 to C2 enrichment (C5/C2), and 3) C5 glucose enrichment after glucagon administration.
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METHODS
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Subjects.
Six healthy males (age 22–31 yr; body mass index 20–25 kg/m2) were studied on three separate occasions after an overnight fast. All subjects were in good health, had no family history of diabetes, and did not use any medication. Participating subjects gave written informed consent. This study was approved by the medical ethics committee of the Academic Medical Center.
Protocol.
Fasting commenced at 7:00 PM (t = 0:00) on the evening before the studies and lasted until 1:00 PM the next day (t = 18:00). Subjects were studied in the supine position. Three studies with different 2H2O incubation periods were performed in each subject (Fig. 1). In each study, blood samples for measurement of gluconeogenesis were drawn at exactly the same time to prevent the influence of diurnal variation of gluconeogenesis on the results. Depending on the study protocol, subjects were studied from t = 14:00 until t = 17:00 in the short incubation study, from t = 12:00 until t = 17:00 in the medium incubation study, and from t = 2:00 until t = 17:00 in the long incubation study. The sequence of studies was determined by random assignment with an interval of 
8 wk between studies to preclude underestimation of fractional gluconeogenesis due to C5 glucose enrichment derived from previous experiments. Before ingestion of 2H2O, a catheter was inserted into an antecubital vein for blood sampling. The hand was kept in a heated hand box at 60°C to allow arterialization of venous blood.
Short 2H2O incubation study, 3 h.
At 8:45 AM, a catheter was inserted into a contralateral antecubital vein for infusion of [6,6-2H2]glucose. After drawing of blood samples for determination of background enrichments of plasma glucose, 2H2O (>99.8% enriched; Cambridge Isotopes, Andover, MA) was ingested every half-hour from 9:00 to 11:00 AM (from t = 14:00 to t = 16:00), up to a total dose of 5 g/kg body water to achieve a plasma 2H2O enrichment of 0.5%. Body water was estimated to be 60% of total body weight. Water consumed during the remainder of the study was enriched with 0.5% 2H2O to maintain isotopic steady state. At 9:00 AM, after taking of a blood sample for background enrichment of plasma glucose, a primed continuous infusion of [6,6-2H2]glucose (>99% enriched, Cambridge Isotopes) was started at a rate of 0.33 µmol·kg–1·min–1 (prime 26.4 µmol/kg). At 11:30 and 11:45 AM, and 12:00 noon (t = 16:30, 16:45, and 17:00) blood samples were drawn for enrichment of [6,6-2H2]glucose, plasma 2H2O enrichment, deuterium enrichment of C5 and C2 enrichment of glucose, glucose concentration, and glucoregulatory hormones. Immediately after the 12:00 noon blood draw, 1 mg (1 IU) of glucagon (Glucagen; Novo Nordisk Farma, Zoeterwoude, The Netherlands) was administered intravenously for 30 s. At 12:15, 12:30, 12:45, and 1:00 PM (t = 17:15, 17:30, 17:45, and 18:00), blood samples were drawn for deuterium enrichment of C5 and C2 enrichment of glucose and glucoregulatory hormones.
Medium 2H2O incubation study, 5 h.
After drawing of blood samples for determination of background enrichments of plasma glucose, 2H2O (5 g/kg body water) was ingested every half-hour from 7:00 to 9:00 AM (from t = 12:00 to t = 14:00). Isotope administration and blood sampling protocol were identical to those in the short 2H2O incubation study.
Long 2H2O incubation study, 15 h.
On the night before the study, after drawing of blood samples for determination of background enrichments of plasma glucose, 2H2O (5 g/kg body water) was ingested every half-hour from 9:00 to 11:00 PM (from t = 2:00 to t = 4:00). Isotope administration and blood sampling protocol were identical to those in the short and medium 2H2O incubation studies.
Gas chromatography-mass spectrometry.
Enrichments of plasma [6,6-2H2]glucose, plasma 2H2O, and deuterium at the C5 and C2 position of glucose were determined as described previously (1). Briefly, plasma samples for glucose enrichments of [6,6-2H2]glucose and glucose concentration were measured as the aldonitril pentaacetate derivative of glucose in deproteinized plasma, using xylose as an internal standard. Glucose was monitored at mass-to-charge ratios (m/z) 187 and 189. The enrichment of [6,6-2H2]glucose was determined by dividing the peak area of m/z 189 by the peak area of m/z 187 and correcting for natural enrichments. To measure deuterium enrichment at the C5 and C2 positions, glucose was converted to hexamethylenetetramine (HMT) as described by Landau et al. (9). HMT was injected into a gas chromatograph-mass spectrometer. Separation was achieved on an AT-Amine column (30 m x 0.25 mm, df 0.25 µm). All isotopic enrichments were measured on a gas chromatograph-mass spectrometer (model 6890 gas chromatograph coupled to a model 5973 mass selective detector, equipped with electron impact ionization mode; Hewlett-Packard, Palo Alto, CA).
Analytic procedures.
Plasma insulin concentration was determined by a chemiluminiscent immunometric assay (Immulite; Diagnostic Products, Los Angeles, CA), intra-assay coefficient of variation (CV) 3–6%, interassay CV 3–5%, detection limit 14 pmol/l. Glucagon was determined by RIA (Linco Research, St. Charles, MO), intra-assay CV 3–5%, interassay CV 9–13%, detection limit 15 ng/l.
Calculation and statistics.
The fractional rate of gluconeogenesis was calculated using two methods: by dividing deuterium enrichment at the C5 position of plasma glucose by plasma 2H2O enrichment and by dividing deuterium enrichment at the C5 position of plasma glucose by deuterium enrichment at the C2 position of plasma glucose. Glucose production before glucagon administration (t = 16:30, 16:45, and 17:00) was calculated by dividing the infusion rate of [6,6-2H2]glucose by the resulting M + 2 tracer-to-tracee ratio of plasma aldonitril pentaacetate glucose, after ascertaining that the M + 2 tracer/tracee ratios were in steady state. Gluconeogenesis was calculated by multiplying fractional gluconeogenesis by glucose production and is expressed as micromoles per kilogram per minute.
Differences between groups and studies were analyzed using the Wilcoxon signed ranks test of SPSS (v.11.5.2; SPSS, Chicago, IL). A P value of <0.05 was considered statistically significant. Data are presented as means ± SD. Plasma 2H2O enrichment and C2 enrichment of glucose were considered equilibrated when no statisticallysignificant difference was found between plasma 2H2O and glucose C2 enrichment.
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RESULTS
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Plasma 2H2O enrichment and C2 enrichment of glucose.
In the short incubation study, plasma 2H2O enrichment and C2 enrichment of glucose were not equilibrated at t = 16:30 and t = 16:45, whereas they were similar at t = 17:00 (2.5- to 3-h incubation). In the medium and long incubation studies, plasma 2H2O enrichment and C2 enrichment of glucose were equilibrated from t = 16:30 to t = 17:00 (4.5- to 5-h incubation in the medium study, 14.5- to 15-h incubation in the long incubation study; Table 1 and Fig. 2).
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Fig. 2. Plasma 2H2O and C2 glucose enrichment in 6 healthy fasted subjects during and after ingestion of 2H2O in the short (3-h), medium (5-h), and long (15-h) incubation studies. *Incomplete equilibration of plasma 2H2O and C2 glucose enrichment.
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The minimum time required to achieve equilibration of 2H2O enrichment and C2 enrichment was 3 h in the short and medium incubation studies and 6 h in the long incubation study.
Fractional gluconeogenesis and gluconeogenesis measured with 2H2O and C2 enrichment.
Fractional gluconeogenesis can be calculated using two methods: by the ratio of C5 and 2H2O enrichment (C5/2H2O) and by the ratio of C5 and C2 enrichment (C5/C2). In the short incubation study, C5/2H2O and C5/C2 were different at t = 16:30 and t = 16:45, whereas they were similar at t = 17:00. In the medium and long incubation studies, C5/2H2O and C5/C2 were similar from t = 16:30 to t = 17:00 (Table 2).
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Table 2. frGNG calculated with C5/2H2O and C5/C2 enrichment in short, medium, and long incubation studies in 6 overnight-fasted males
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Gluconeogenesis was calculated by multiplying glucose production by C5/2H2O and multiplying glucose production by C5/C2. In the short incubation study, gluconeogenesis calculated with C5/2H2O was consistently lower than gluconeogenesis calculated with C5/C2 from t = 16:30 to t = 17:00. In the medium and long incubation studies, gluconeogenesis calculated with C5/2H2O and C5/C2 was similar from t = 16:30 to t = 17:00 (Tables 3 and 4)
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Table 3. GNG calculated with 2H2O and C2 enrichment in short, medium, and long incubation studies in 6 overnight-fasted males
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Table 5. Glucose, glucagon, and insulin concentrations before and after 1 mg iv glucagon administration at 12:00 noon in 6 overnight-fasted males
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Glucagon administration: C5 and C2 enrichment of glucose and fractional gluconeogenesis.
Before glucagon administration at t = 17:00, C5 enrichment was similar in the short, medium, and long incubation studies. After glucagon administration, C5 enrichment was not different between any of the studies from t = 17:15 to t = 18:00, nor was the area under the curve of C5 different between studies (short vs. medium P = 0.69; short vs. long P = 0.68; medium vs. long P = 0.79). Although no differences in C5 enrichment between the incubation studies were observed, administration of glucagon did cause changes in C5 enrichment compared with the baseline C5 enrichment at t = 17:00 in individual incubation studies. In the short incubation study, glucagon tended to decrease C5 enrichment at t = 17:15 and t = 17:30 (P = 0.07 and P = 0.07, respectively). In the medium incubation study, no changes in C5 enrichment were observed. In the long incubation study, C5 enrichment was decreased at t = 17:15, 17:30, and at 17:45 (P = 0.04, 0.03, and 0.04, respectively) and tended to be decreased at t = 18:00 (P = 0.08; Table 6).
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Table 6. C5 and C2 enrichment (%) and frGNG in short, medium, and long incubation studies before and after 1 mg iv glucagon administration at 12:00 noon in 6 overnight-fasted males
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C2 enrichment was similar in the short, medium, and long incubation studies before and after glucagon administration and was not influenced by glucagon in any of the individual studies compared with baseline values at t = 17:00.
Fractional gluconeogenesis (C5/C2) was not different between the short, medium, and long incubation studies before and after glucagon administration. Some of the changes seen in C5 enrichment after the administration of glucagon were reflected in fractional gluconeogenesis: in the short incubation study, fractional gluconeogenesis tended to be decreased at t = 17:30 (P = 0.08) compared with baseline at t = 17:00. In the medium incubation study, no changes were observed, whereas in the long incubation studies fractional gluconeogenesis was decreased or tended to be decreased from t = 17:15 onward (P = 0.04, 0.07, 0.07, and 0.04 at t = 17:15, 17:30, 17:45, and 18:00, respectively; Table 6).
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DISCUSSION
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This study shows that 3 h of 2H2O incubation in the short study was insufficient to completely equilibrate plasma 2H2O and C2 glucose enrichment. Fractional gluconeogenesis calculated using the C5/2H2O ratio tended to be lower than the C5/C2 ratio due to incomplete equilibration in the short study. This difference is ultimately reflected in calculated rates of gluconeogenesis. After 5 and 15 h of 2H2O incubation, equilibration of plasma 2H2O enrichment and C2 glucose enrichment was achieved, and C5/2H2O and C5/C2 and calculated rates of gluconeogenesis were similar. Gluconeogenetic labeling of hepatic glycogen did not appear to have influenced the measurement of gluconeogenesis in any of the studies, as no differences in C5 glucose enrichment between the studies were found after administration of glucagon.
The prerequisite for calculating fractional gluconeogenesis with C5/2H2O instead of C5/C2 is the complete equilibration of plasma 2H2O enrichment with C2 glucose enrichment. Equilibration of plasma 2H2O and C2 enrichment indicates equilibration of 2H2O with the intrahepatic glucose 6-phosphate pool. The present study shows that 3 h of 2H2O incubation in the short incubation study is barely enough to achieve complete equilibration: the plasma 2H2O enrichment was lower than the C2 glucose enrichment at t = 16:30 and t = 16:45 and was scarcely equilibrated at t = 17:00. Because the last 2H2O dose was ingested half an hour before the first sample for isotopic enrichment was drawn at t = 16:30, incomplete equilibration was most likely due to insufficient time for incorporation of deuterium label into endogenously produced glucose. Results from the medium and long incubation studies indicate that 5 and 15 h of 2H2O incubation are sufficient to reach equilibration, enabling reliable calculation of gluconeogenesis with the C5/2H2O ratio. Figure 2 depicts the equilibration of plasma 2H2O and C2 glucose enrichment over time and shows that equilibration in the short and medium incubation studies was only just achieved after 3 h of incubation. However, in the long incubation study, 6 h of incubation was needed for equilibration. Although this remarkable difference remains unexplained, it could be due to the relatively short time of fasting during 2H2O incubation and indicates that fasting period also plays a role in the equilibration of plasma 2H2O and C2 glucose enrichment. In the long incubation study, 2H2O was ingested 2 h after the last meal, when the subjects were still in the absorptive state. The absorptive state is characterized by influx of exogenous glucose, high insulin levels, and suppressed glucose production and generally lasts for 4 h until the postabsorptive state is reached, which is characterized by decreased insulin levels and increased glucose production. Although glucose production was not investigated until 16.5 h of fasting, suppressed glucose production could have disturbed the equilibration of plasma 2H2O and C2 glucose enrichment by decreasing the appearance of C2-labeled glucose in plasma. To elucidate whether the fasting period does indeed influence the equilibration of plasma 2H2O and C2 glucose, further research seems warranted.
No conclusions can be safely drawn about the shortest required 2H2O incubation period as the equilibration of plasma 2H2O and C2 glucose enrichment is variable and different between studies. In the short incubation study, equilibration of plasma 2H2O and C2 glucose enrichment was only just achieved after 3 h of incubation but proved to yield an unreliable measurement of gluconeogenesis. Figure 2 suggests a minimum incubation period of 3 h in the medium incubation study and 6 h in the long study. Although the shortest incubation period cannot be pinpointed in the present study, it can be concluded that a 2H2O incubation period greater than 3 h is required when 2H2O is ingested in the postabsorptive state.
Gluconeogenetic labeling of hepatic glycogen cannot be excluded, as glucagon administration had different effects on C5 glucose enrichment in each of the incubation studies: a tendency to decrease in the short incubation study, no effect in the medium incubation study, and a decrease in the long incubation study. Because glucagon is a powerful stimulator of glycogenolysis, the observed decrease in C5 enrichment is likely to have been caused by increased glycogenolysis at the cost of gluconeogenesis. It remains unclear why glucagon administration did not affect C5 enrichment in the medium incubation study. Although some gluconeogenetic labeling of hepatic glycogen during 2H2O incubation cannot be excluded, its effect on the measurement of gluconeogenesis is limited, as no differences of C5 enrichment before and after glucagon administration were found between the short, medium, and long incubation studies.
In conclusion, for reliable measurement of gluconeogenesis with C5/2H2O, longer 2H2O incubation periods are required: 3 h of 2H2O incubation was insufficient, whereas 5 and 15 h of 2H2O incubation were sufficient to reliably measure gluconeogenesis with C5/2H2O. Furthermore, our data also indicate that the fasting period could influence the degree of equilibration. When gluconeogenesis is measured after an overnight fast an equilibration time of 5 h is sufficient for reliable measurement of gluconeogenesis with C5/2H2O. With shorter fasting periods, a minimum of 6 h of equilibration is recommended. Gluconeogenetic labeling of glycogen did not affect the results after 3, 5, or 15 h of 2H2O incubation.
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ACKNOWLEDGMENTS
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We thank An Ruiter and Barbara Voermans for excellent analytic support.
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FOOTNOTES
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Address for reprint requests and other correspondence: G. Allick, Dept. of Endocrinology and Metabolism, Academic Medical Center, PO Box 22700, 1100 DD Amsterdam, The Netherlands (e-mail: g.allick{at}amc.uva.nl)
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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