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Original Studies |
Department of Clinical Chemistry, Laboratory of Endocrinology and Radiochemistry (M.T.A., E.E.), and Department of Internal Medicine and Endocrinology (P.H.B., H.P.S.), Academic Medical Center, University of Amsterdam, 1100 DD Amsterdam; and Department of Endocrinology, Leiden University Medical Center (A.M.P.A., P.H.B., J.A.R.), Leiden, 2300 RC The Netherlands
Address all correspondence and requests for reprints to: M. T. Ackermans, Ph.D., Department of Clinical Chemistry, Laboratory of Endocrinology and Radiochemistry, F2-111, Academic Medical Center, P.O. Box 22660, 1100 DD Amsterdam, The Netherlands. E-mail: m.t.ackermans{at}amc.uva.nl
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The application of radioactive and stable isotopes for the measurement of GNG is attractive, because of the simple and noninvasive study design. However, conceptual problems in the application of these isotopes for this purpose have been recognized for many years. The application of labeled gluconeogenic precursors such as alanine, pyruvate, and lactate suffers from the limitation that these tracers are diluted in the relatively rapidly turning over oxaloacetate pool before conversion to glucose. Moreover, in the calculation of GNG the enrichment of the precursor pool for GNG, the oxaloacetate pool, has to be taken into account, which cannot be measured directly (3) Isotopic exchanges in the oxaloacetate pool result in dilution of the labeling (4). Consequently, these isotope approaches are limited by assumptions regarding the enrichment of this oxaloacetate pool.
In recent years three different stable isotope methods for the quantification of fractional GNG have been described that bypass the problems of the oxaloacetate precursor pool enrichment, namely mass isotopomer distribution analysis (MIDA) based on infusion of [2-13C]glycerol or [U-13C]glucose, and the deuterated water method. Hellerstein et al. infused [2-13C]glycerol and measured the enrichment and mass isotope distribution of 13C in glucose. In this method enrichment of the precursor pool of GNG, the triose phosphate pool, was derived by the principles of the MIDA (5). Questions have been raised about the validity of MIDA to measure fractional GNG, because of metabolic zonation in the liver with concomitant decreases in concentration and enrichment of glycerol across the liver lobule (6, 7, 8). Homogeneity of the precursor pool is a key condition of validity for the MIDA technique, as enrichment of the precursor must be the same in all cells that synthesize the calculated biopolymer, in this case glucose.
Another method to quantify GNG by MIDA, based on the use of [U-13C]glucose, was reported by Tayek and Katz (9). According to Landau et al. (10), however, this method underestimated gluconeogenesis, because underlying assumptions apparently could not be fulfilled, and the contribution of GNG from glycerol and amino acids was ascribed to glycogenolysis. Recently, Katz and Tayek (11) presented and discussed their questioned approach by publishing a theoretical analysis of recycling and concluded that their method was correct. Nevertheless, again Landau (12), Kelleher (13), and Radziuk and Lee (14) questioned the presentation and stated that this approach was invalid.
The administration of 2H2O according to the method of Landau measures the enrichment of deuterium in specific positions in glucose, namely C2 and C5 (15, 16). Because the exchange of deuterium between the gluconeogenic precursors and body water occurs after passing through the oxaloacetate pool, this method also does not involve the limitations of the unknown enrichment of this pool. Although the methods of both Hellerstein et al. and Landau et al. are very attractive, a direct comparison of these two different approaches has not been performed.
In previous studies we applied the [2-13C]glycerol and 2H2O methods in separate study designs, which did not enable a comparison between the two methods (17, 18, 19). To elucidate the uncertainty concerning the comparison of these methods for quantifying GNG, we compared these two techniques directly in six healthy males after a 14-h fast.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Six healthy male volunteers, aged 26–54 yr, were studied. Their weights ranged from 60–95 kg (body mass index, 20.0–24.5 kg/m2). The volunteers were studied on three separate occasions; in a randomized balanced design GNG was measured by the 2H2O method (without the infusion of unlabeled glycerol) and by the [2-13C]glycerol method. The time interval between the studies was 2 weeks. Several months after the other two experiments, GNG was measured during the infusion of unlabeled glycerol by the 2H2O method. For 3 days preceding each study the volunteers ingested a strictly standardized eucaloric diet composed of 13% proteins, 48% carbohydrates, and 39% fat (Nutridrink, Nutricia, Zoetermeer, The Netherlands), with the last intake at 2200 h on the evening before the study. On the morning of the 2H2O study at 0800 h the subjects ingested 1 g/kg body water 2H2O (99% pure, Cambridge Isotopes, Cambridge, MA) at intervals of 30 min until a total dose of 5 g/kg body water was reached. Body water was estimated to be 60% of body weight. At 1000 h a primed (26.4 µmol/kg) continuous infusion of [6,6-2H2]glucose (0.33 µmol/kg·min; 99% enriched, Cambridge Isotopes) was started. Arterialized blood for the measurement of background enrichments was drawn at 0800 and 1000 h and for isotope analyses and analysis of the glucoregulatory hormones at 1200, 1230, and 1300 h. Urine was collected at 0800 h for background enrichment and from 1200–1300 h for determination of deuterium enrichment in body water. Water, ingested ad libitum throughout the study, was enriched with 0.5% 2H2O to maintain the steady state of 0.5% deuterium enrichment in body water. On the morning of the [2-13C]glycerol study, a primed (190 µmol/kg) continuous infusion of [2-13C]glycerol (3.15 µmol/kg·min; 99% enriched, Cambridge Isotopes) was started at 0900 h. At 1000 h a primed (26.4 µmol/kg) continuous infusion of [6,6-2H2]glucose (0.33 µmol/kg·min) was started. Arterialized blood for background enrichments was drawn at 0900 h, and that for isotope analyses and analysis of glucoregulatory hormones was drawn at 1200, 1230, and 1300 h. As mentioned earlier, all volunteers were also studied on a third occasion to exclude an effect of the amount of glycerol infused on total glucose production and gluconeogenesis. The protocol of this study was the same as that on the 2H2O study day, except for the fact that a primed (190 µmol/kg) continuous infusion of unlabeled glycerol (3.15 µmol/kg·min) was started at 0900 h and continued till 1300 h. To show that the 2-h equilibration period for 2H2O is sufficient in this protocol, we measured plasma water enrichment every 15 min from 0800–1000 h and then every 30 min until 1300 h. One additional sample was taken at 1600 h.
Sample preparation
2H2O method.
The glucose concentration and
[6,6-2H2]glucose
enrichment in the samples were measured using a method adapted from
Reinauer et al. (20). Twenty-five microliters
of xylose (10 mmol/L) were added to the plasma samples (50 µL) as an
internal standard. Using equimolar solutions the abundance of the
xylose signal will be approximately 1.5 times the abundance of the
glucose peak. The samples were deproteinized by mixing with 1 mL
methanol. After centrifugation, the supernatant was evaporated to
dryness under a stream of N2. The aldonitrile
pentaacetate derivative of glucose and the aldonitrile tetraacetate
derivative of xylose were prepared with 100 µL hydroxylamine in
methanol (5 mg hydroxylamine and 12.5 mg sodium acetate in 1 mL
methanol), and the mixture was heated for 60 min at 60 C. After drying
the sample under a stream of N2, 100 µL acetic
anhydride were added, and the sample was heated for another 60 min at
120 C. The reaction mixture was cooled and partitioned between water
(750 µL) and methylenechloride (750 µL). The lower
methylenechloride layer was dried and reconstituted in ethylacetate,
which was injected into the gas chromatograph (model 6890 gas
chromatograph coupled to a model 5973 mass selective detector, equipped
with an electron impact ionization mode, Hewlett-Packard Co., Palo Alto, CA). For determination of the glucose
concentration a calibration graph using the internal standard method
was used. The columns used and the gas chromatographic and mass
spectrometric conditions are given in Table 1
. The enrichment of
[6,6-2H2]glucose was
determined by dividing the peak area at M+2 by the total peak area of
the glucose aldonitrile pentaacetate peak, and correction for the
natural abundance was performed by subtracting the natural abundance
from the measured M+2 enrichment.
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In addition to the original method, we performed an adaptation to
evaluate whether the use of calibration solutions is necessary. The
principle of MIDA can be used to calculate enrichments if the molecule
measured can be interpreted as a polymer. In the case of the
[2-13C]glycerol method, the glucose
molecule is seen as a dimer of two triose molecules. In the case of the
2H2O method, the HMT
molecule can be seen as hexamer of the formaldehyde molecule. This
implies that using a theoretical table, the distribution over the
different masses of the HMT molecule (M0, M1, M2, etc.) can
be calculated starting from the enrichment in formaldehyde, originally
derived from the glucose molecules. Using this table the enrichment at
the C5 position can be calculated from the measured excess M1 (EM1) in
the HMT molecule, making a calibration curve superfluous. As shown in
Table 2, there were no significant
differences between the enrichment on the C5 position as determined
using the method described by Landau et al.
(16) and the value obtained using the calculated MIDA
table for HMT. Therefore, the calculated table can be used instead of
the laborious use of calibration solutions.
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). The deuterium enrichment in body water was measured in
acetylene formed through the reaction of body water and calcium
carbide, as described by van Kreel et al. (21).
The enrichment in plasma water was measured in the same way, handling
the plasma as if it were urine.
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.The glucose pentaacetate derivative was
used instead of the aldonitrile pentaacetate derivative, because for
this derivative it is easier to keep the values of unenriched glucose
within the 3% levels of the theoretical ones, and this derivative
gives two peaks for glucose (
- and ß-anomer), resulting in a
duplicate value for one sample. The fractional GNG was calculated as:
fractional GNG = EM1/A11,
where A11 is the maximum EM1
that can be reached for the measured precursor pool enrichment
(5). To measure the glucose concentration in the sample, we prepared the samples a second time, this time adding xylose to the sample at a final concentration of 3.33 mmol/L as the internal standard. A calibration graph using the internal standard method was constructed for the glucose concentration using standard solutions of glucose in water. Addition of xylose as an internal standard for determination of the glucose concentration did not influence the results for triose phosphate pool enrichment or the results for the relative contribution of GNG to the EGP. Using the calibration solutions, the glucose concentration in the plasma samples can be measured in one analytical run together with the [6,6-2H2]glucose enrichment.
Glycerol concentration and glycerol enrichment
The glycerol concentration and [2-13C]glycerol enrichment during [2-13C]glycerol infusion were measured as described previously (23). With an enzymatic method (Roche, Mannheim, Germany) the glycerol concentration was measured in all samples at 1200 h.
Glucoregulatory hormones
The plasma insulin concentration was measured by commercial RIA
(Pharmacia Biotech, Uppsala, Sweden), C peptide by
125I RIA (Byk Sangtec, Dietzenbach, Germany),
plasma cortisol levels by fluorescence polarization immunoassay on
technical device X (Abbott Laboratories, Chicago, IL), GH
by chemiluminescence immunometric assay (Nichols Institute Diagnostics, San Juan Capistrano, CA), glucagon by RIA
(Linco Research, Inc., St. Charles, MO; glucagon antiserum
elicited in guinea pigs against pancreatic specific glucagon;
cross-reactivity with glucagon-like substances of intestinal origin,
<0.1%), and plasma epinephrine and norepinephrine by high performance
liquid chromatography with fluorescence detection, using -methyl
norepinephrine as an internal standard (24).
Statistics
Data were analyzed by a two-sided nonparametric test for paired samples (Wilcoxon matched pairs test). P < 0.05 was considered to represent a significant statistical difference.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Plasma glucose concentrations were not different between the
[2-13C]glycerol and the
2H2O studies. Starting
values were 5.0 ± 0.5 mmol/L on the
[2-13C]glycerol day vs. 5.3 ±
0.5 mmol/L on the 2H2O day.
Table 3 gives the measured M1 and M2
values for the different molecules during the respective protocols. The
calculated values for triose phosphate precursor pool enrichment (p),
percentage GNG (f), and
[6,6-2H2]glucose
enrichment on the [2-13C]glycerol study day and
the measured values for deuterium enrichment on C5 position, total body
water enrichment, plasma water enrichment, and
[6,6-2H2]glucose
enrichment on the 2H2O
study day are given in Table 4. The rates
of EGP and GNG for the six subjects are given in Table 5. EGP was not different between the
methods (12.2 ± 0.7 on the
2H2O day vs.
11.7 ± 0.3 µmol/kg·min on the
[2-13C]glycerol day). However, GNG as measured
in both methods was different (7.4 ± 0.7 on the
2H2O day vs.
4.9 ± 0.6 µmol/kg·min on the
[2-13C]glycerol day; P = 0.03).
GNG represents 60.4 ± 6.9 on the
2H2O day
vs. 41.0 ± 5.3% on the
[2-13C]glycerol day of EGP after an
overnight fast. Data for the glycerol concentration,
[2-13C]glycerol enrichment, and glycerol
turnover on the day of the [2-13C]glycerol
protocol are given in Table 6. There was
no difference in measured plasma values of the glucoregulatory hormones
(insulin, cortisol, C peptide, GH, glucagon, and catecholamines)
between the 2 study days (Table 7).
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Table 3 gives the measured M1 and M2 values for the different
molecules during the respective protocols. The measured values for
deuterium enrichment on C5 position, total body water enrichment,
plasma water enrichment, and
[6,6-2H2]glucose
enrichment on both study days are given in Table 4. The rates of EGP
and GNG for the six subjects are given in Table 5. EGP was not
different between the methods (12.2 ± 0.7 µmol/kg·min without
glycerol vs. 12.3 ± 1.1 µmol/kg·min with glycerol
infusion). Infusion of unlabeled glycerol increased the glycerol
concentration in plasma by about 200% (188 ± 29 vs.
67 ± 7 µmol/L), comparable to the concentration obtained during
infusion of [2-13C]glycerol (190 ± 26
µmol/L). GNG was not affected by glycerol infusion (7.4 ± 0.7
µmol/kg·min without glycerol infusion vs. 7.6 ±
0.9 µmol/kg·min with glycerol infusion). GNG represented 60 ±
7% without glycerol infusion vs. 62 ± 7% with
glycerol infusion of EGP after an overnight fast. There were no
differences in measured plasma values of the glucoregulatory hormones
(insulin, cortisol, C peptide, GH, glucagon, and catecholamines)
between the study days (Table 7).
Equilibration of 2H2O
In Fig. 1 the enrichments of plasma
water as measured during the
2H2O protocol with glycerol
infusion are given, clearly demonstrating that steady state was reached
1 h before EGP/GNG analyses.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our data from the [2-13C]glycerol method are in good agreement with the data provided by the original publications; the rate of GNG represents about 36% of EGP in 11-h fasted subjects (22). Using the 2H2O method, our data show GNG percentages comparable to those reported by Landau (60% in our study vs. 47–60%) (16, 25, 26). Therefore, when comparing the data in the original publications, the rates of GNG yielded by both methods seem to be different (3), with the 2H2O data yielding higher or, conversely, the [2-13C]glycerol data yielding lower rates of GNG.
Although the MIDA technique is a brilliant technique to measure the
synthesis of biopolymers, this technique cannot be applied
indiscriminately, especially for the synthesis of a biopolymer in an
organ with metabolic zonation such as the liver. A major assumption in
the application of MIDA to measure fractional GNG is that there
is a single triose phosphate pool. The literature data about the
existence of such a single triose phosphate pool are contradictory.
Landau et al. found that the isotopomer distributions in
glucose and glucuronic acid from urinary acetaminophen
glucuronide on administration of
[U-13C]glycerol were incompatible with GNG from
a single pool of triose phosphates, which is required for MIDA
(6). In contrast, Neese et al.
(27) and Hellerstein et al. (28)
found that the ratios of doubly labeled/singly labeled
13C in glucose and glucuronide after infusion of
[2-13C]glycerol were identical in rats and
humans, supporting the contention of a single triose phosphate pool.
Their findings were supported by Peroni et al., who tested
the validity of the MIDA approach by
[2-13C]glycerol in rats in vivo and
in vitro (29). Neese et al. and
Peroni et al. calculated contributions of close to 100% in
rats starved for 2 days (16, 27, 29). In contrast, Landau
et al. using [U-13C]glycerol
calculated a fractional contribution of GNG to glucose production of
only approximately 60% in 60-h fasted humans (6). In
accordance with Landau et al., Previs et al.
observed a fractional contribution of GNG of 36–64% using
[U-13C]glycerol or
[U-13C]lactate in vivo in rats
starved for 2 days, and 84–85% with
[2-13C]glycerol in perfused livers of rats
starved for 2 days (7). Several explanations have been
provided to explain these discrepancies among the different studies
employing MIDA in the quantification of fractional GNG. Because there
is a marked transhepatic gradient of glycerol, Landau et al.
hypothesized that there is a progressive decrease in the labeling of
triose phosphates from the periportal to the perivenous region of the
liver lobules (6). Different infusion rates of the
glycerol tracer could result in differences in the concentration
gradient of glycerol across the liver. In accordance with this
hypothesis, Previs et al. observed a higher fractional
contribution of GNG with increasing glycerol concentrations in liver
perfusate (7). However, recently they showed that in
vitro the 13C labeling of triose was not
equal in all (rat) hepatocytes, even when they were exposed to the same
substrate concentrations and enrichment (30). They
therefore concluded that zonation of processes other than glycerol
phosphorylation contributes to the heterogeneity of triose phosphate
labeling from glycerol. Nevertheless, the same group recently reported
that in mice reasonable estimates are only obtained at glycerol
infusion rates sufficiently high to perturb glucose and glycerol
metabolism (8, 31). Accordingly by flooding the liver by
relatively high glycerol tracer infusion rates to achieve hepatic
precursor pool enrichments above 0.10 as done in our study (see also
Table 6), the risk of significant underestimation of GNG seemed less
probable, as discussed by Christiansen et al
(38). Because we did not infuse
[2-13C]glycerol in tracer amounts, we performed an
additional experiment with unlabeled glycerol. We showed that in humans
the amount of glycerol used in the
[2-13C]glycerol method does not affect
endogenous glucose production, in agreement with the literature
(39, 40). Although there are signs that increased
supply of gluconeogenetic precusors can augment the percent
gluconeogenesis of the total glucose production
(39), glycerol infusion per se does not affect
fractional gluconeogenesis measured by the
2H2O method.
The differences in the rates of GNG measured by the two approaches are the result of underestimation by the [2-13C]glycerol method (see above) and/or overestimation by the 2H2O method. Analytical problems related to the simultaneous administration of 2H2O and [6,6-2H2]glucose do not seem to be involved, because Chandramouli et al. showed that this did not affect the measurement of the enrichments at C2, C5, and C6 of glucose (25). Overestimation of GNG by the 2H2O method might involve processes other than GNG causing erroneously low values for C2 enrichment and/or erroneously high values for C5 enrichment in plasma glucose. Gluconeogenesis using the C5/C2 ratio will be overestimated by the degree of cycling between glucose-6-phosphate and triose phosphate, and/or loss of label via transaldolase exchange reactions that are part of the pentose cycle (26). The contribution of the cycling between glucose-6-phophate and triose phosphate resulting in an increase in the labeling of C5 and, thus, in an overestimation of gluconeogenesis, measured with deuterated water, has been estimated by Landau to be 2–3% (26). This cycling is probably less of a possibility for obtaining an aberrant estimation of gluconeogenesis by MIDA, as changes in M1 and M2 enrichment in this cycle will be at random, without a systematic change in a certain direction. Cycling of glucose-6-phosphate in the pentose cycle has been judged to give a similar overestimation (33). Recently, however, Kurland et al. (41) reported that recycling of glucose carbons through the pentose phosphate cycle during gluconeogenesis is very large, implicating that the activity of the pentose phosphate cycle may result in larger overestimation than previously expected (34). For the same reason as given above, pentose phosphate cycling will not influence the measurement of fractional gluconeogenesis by MIDA. Finally, it should be noted that glycogen cycling, i.e. the cycling between blood glucose through the liver and back, is a physiological complicating factor that affects the 2H2O and the [2-13C]glycerol method equally. Therefore, glycogen cycling is not a factor involved in the explanation of the different results obtained by both methods.
Unfortunately, there is no gold standard for measuring gluconeogenesis in vivo in humans to which the isotope data can be compared. Consequently, the only possible approach is to compare different techniques. In physiological conditions the 2H2O method and the [13C]-NMR technique show perfect agreement in the estimation of fractional GNG (2, 35), but this is not the case when the two methods are applied to pathological conditions [liver cirrhosis (26)]. However, this discrepancy can be attributed to a difference in definition. Using the 2H2O (or the [2-13C]glycerol) method, the GNG measured is glucose production-glycogenolysis. In the 13C-NMR technique the net glycogenolysis (glycogenolysis-glycogenesis) is measured, the GNG being glucose production-net glycogenolysis. When there is no glycogenesis [as in normal fasted subjects (42)], the stable isotope techniques and the 13C-NMR should give the same results. In those cases where glycogen synthesis occurs, GNG measured by 13C-NMR will be greater than that measured by the stable isotope techniques to the extent that glycogenesis occurs.
Some remarks can be made about the practical implications of both methods. Drawbacks of the [2-13C]glycerol method are the expense of the isotopes and the rather complicated calculations involved in the MIDA. On the other hand, the 2H2O method involves much more complicated and time-consuming laboratory methods. The deuterated water method can also not be repeated within short intervals, as the method requires complete removal of the isotope from the body (36), a feature that takes weeks. Another practical difference between both methods is that the 2H2O method requires more blood and is therefore not applicable in some conditions, i.e. in small children (37).
In conclusion, the 2H2O and [2-13C]glycerol methods yield consistently different results of fractional gluconeogenesis in the postabsorptive state. Although a gold standard for the measurement of GNG is lacking, the agreement with 13C-NMR provides an argument in favor of the 2H2O method in physiological conditions, but not in pathological conditions. Obviously, in the comparison of data for gluconeogenesis in different studies, only data obtained with the same method of measurement should be taken into consideration.
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Acknowledgments |
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Footnotes |
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Received March 30, 2000.
Revised July 27, 2000.
Revised November 30, 2000.
Accepted December 6, 2000.
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 H. van Thien, M.T. Ackermans, E. Dekker, V.O. T. Chien, T. Le, E. Endert, P.A. Kager, J.A. Romijn, and H.P. Sauerwein Glucose production and gluconeogenesis in adults with cerebral malaria QJM, December 1, 2001; 94(12): 709 - 715. [Abstract] [Full Text] [PDF]
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 T. H. van Dijk, F. H. van der Sluijs, C. H. Wiegman, J. F. W. Baller, L. A. Gustafson, H.-J. Burger, A. W. Herling, F. Kuipers, A. J. Meijer, and D.-J. Reijngoud Acute Inhibition of Hepatic Glucose-6-phosphatase Does Not Affect Gluconeogenesis but Directs Gluconeogenic Flux toward Glycogen in Fasted Rats. A PHARMACOLOGICAL STUDY WITH THE CHLOROGENIC ACID DERIVATIVE S4048 J. Biol. Chem., July 6, 2001; 276(28): 25727 - 25735. [Abstract] [Full Text] [PDF]
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