1 Schwartz Center for Metabolism and Nutrition, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44109; and 2 Erasmus University and Sophia Children's Hospital, 3000 CB Rotterdam, The Netherlands
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ABSTRACT |
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The rate of
glucose turnover (Ra) and gluconeogenesis (GNG) via
pyruvate were quantified in seven full-term healthy babies between 24 and 48 h after birth and in twelve low-birth-weight infants on
days 3 and 4 by use of
[13C6]glucose and
2H2O. The preterm babies were receiving
parenteral alimentation of either glucose or glucose plus amino acid
with or without lipids. The contribution of GNG to glucose production
was measured by the appearance of 2H on C-6 of glucose.
Glucose Ra in full-term babies was 30 ± 1.7 (SD)
µmol · kg1 · min
1. GNG
via pyruvate contributed ~31% to glucose Ra. In preterm babies, the contribution of GNG to endogenous glucose Ra
was variable (range 6-60%). The highest contribution was in
infants receiving low rates of exogenous glucose infusion. In an
additional group of infants of normal and diabetic mothers, lactate
turnover and its incorporation into glucose were measured within
4-24 h of birth by use of [13C3]lactate
tracer. The rate of lactate turnover was 38 µmol · kg
1 · min
1, and
lactate C, not corrected for loss of tracer in the tricarboxylic acid
cycle, contributed ~18% to glucose C. Lactate and glucose kinetics
were similar in infants that were small for their gestational age and
in normal infants or infants of diabetic mothers. These data show that
gluconeogenesis is evident soon after birth in the newborn infant and
that, even after a brief fast (5 h), GNG via pyruvate makes a
significant contribution to glucose production in healthy full-term
infants. These data may have important implications for the nutritional
support of the healthy and sick newborn infant.
gluconeogenesis; lactate; stable isotopes; newborn infants; 2H2O
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INTRODUCTION |
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THE FETUS IN UTERO, under normal unperturbed physiological circumstances, is entirely dependent on the mother for a continuous supply of glucose, and no significant production of glucose by the fetus has been demonstrated, either in human or in other mammalian species (see review in Ref. 15). In addition, although significant activity of key enzymes involved in gluconeogenesis has been documented early in gestation in human fetal liver, gluconeogenesis in vivo has not been documented (11, 19, 29, 32, 33). Whether cytosolic phosphoenolpyruvate carboxykinase, the key regulatory enzyme involved in gluconeogenesis, is expressed in human fetal liver is not known. In rodents, cytosolic phosphoenolpyruvate carboxykinase is first expressed immediately after birth and is associated with the appearance of gluconeogenesis (12, 15). Thus the newborn at birth relies entirely on the mobilization of accumulated hepatic glycogen stores and the initiation of gluconeogenesis for a continuous supply of glucose. Both of these processes, i.e., glycogenolysis and gluconeogenesis, are stimulated by the birth-associated surges of catecholamines and pancreatic glucagon (20). That the human newborn can incorporate alanine carbon into glucose as early as 6 h of age has been demonstrated by Frazer et al. with a 13C-labeled tracer (10). However, the contribution of gluconeogenesis to glucose production in healthy full-term newborns has not been quantified. In the present study, with stable isotopic tracers, we have quantified the turnover rate of lactate and its incorporation into glucose in the period immediately after birth. In addition, using the recently developed deuterium-labeled water method (4, 22, 27), we have quantified the contribution of gluconeogenesis via pyruvate to total glucose production in healthy, normal full-term babies. During adaptation to the extrauterine environment, perturbations in glucose homeostasis are often observed in preterm infants, in those born small for gestational age, and in those born to mothers with diabetes (20). Because both hyperglycemia and hypoglycemia are often seen in these babies, we also quantified the rates of glucose turnover and gluconeogenesis in clinically stable infants in these groups. Our data show that gluconeogenesis from lactate and pyruvate is established by 4-6 h after birth. Gluconeogenesis from pyruvate contributes as much as 30% to total glucose production in healthy term babies between 5 and 6 h after a feed.
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MATERIALS AND METHODS |
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Gluconeogenesis (GNG) was measured in normal, preterm, small-for-gestational-age (SGA) infants, and in infants of diabetic mothers either by use of the deuterium labeling of body water or by quantifying the incorporation of 13C from labeled lactate into glucose.
Deuterium-Labeled Water Studies
GNG was quantified in seven full-term infants and thirteen preterm infants with the method of deuterium labeling of body water (4, 27). The study protocol was approved by the institutional review board. Written informed consent was obtained from the mother and, when available, the father, after the procedure had been fully explained. The full-term infants were appropriate for gestational age, had normal Apgar scores, had no clinical problems, and were receiving either formula feeds or maternal breast milk (Table 1). Two infants (nos. 6 and 7) were born to mothers with gestational and insulin-dependent diabetes mellitus (IDDM). They had normal plasma glucose concentrations and did not develop any neonatal problems.
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A majority of the term infants were studied on the 2nd day after birth
in the General Clinical Research Center at MetroHealth Medical Center
(Cleveland, OH). Two indwelling cannulas were placed in the superficial
vein of each hand to draw blood samples and infuse the isotopic tracer
[13C6]glucose (99% 13C; Isotec,
Miamisburg, OH). The study protocol is displayed in Fig.
1. Approximately 3 h after the last
feed, an oral dose (4 g/kg body wt) of 2H2O
(99% 2H; Isotec) mixed with sterile distilled water was
administered. Two hours later, three blood samples for the measurement
of [2H]enrichment of C-6 of plasma glucose were obtained
at 20-min intervals. This was followed by intravenous administration of a prime constant-rate infusion of
[13C6]glucose for the next 120 min to
quantify the rate of appearance (Ra) of glucose. The bolus
prime was 0.6 mg/kg body weight, and the constant rate infusion was 30 µg · kg1 · min
1. Blood
samples were obtained for the measurement of glucose
m6 enrichment at 90, 105, and 120 min of
[13C6]glucose infusion. The infants were
comfortable throughout the study period and did not show any evidence
of stress. Cardiopulmonary monitoring was performed and plasma glucose
concentration measured with each blood sampling. Their plasma glucose
concentration remained unchanged throughout the study. The blood
samples were centrifuged at 4°C, and plasma was stored at
70°C for later analysis. The study was completed at ~8 h after
the last feed. In one infant (no. 8, not reported here), the
study was discontinued because of inability to obtain venous blood
samples.
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The preterm infants were studied between 48 and 72 h after birth
with a similar protocol as described above, with minor modifications. As anticipated, all preterm infants were initially on ventilatory support. At the time of study, three infants were on ventilatory support and one required continuous positive airway pressure. No babies
were on vasopressors at the time of study. All were receiving
antibiotics, and three were on caffeine due to apnea or prematurity.
All had indwelling vascular cannulas for clinical indications. Within
24 h after birth, they were assigned to either glucose, glucose
plus amino acids (1.2 g · kg1 · day
1), or
glucose, amino acids (1.2 g · kg
1 · day
1), and lipids
(1.25 g · kg
1 · day
1 = ~1 µmol · kg
1 · min
1).
The rate of glucose infusion was based on the clinical protocol and
adjusted by the patient's physician on the basis of clinical and
laboratory information. However, the rate of glucose infusion was
constant for several hours before and throughout the tracer infusion
study. Plasma samples for deuterium enrichment on C-6 of glucose were
obtained 3, 4, and 5 h after the nasogastric dose of
2H2O. [13C6]glucose
infusion was started at 5 h, and blood samples for the
13C enrichment of glucose were obtained at 6.5, 6.75, and
7 h of the study. The doses of 2H2O and
[13C6]glucose were the same per kilogram of
body weight as for term infants. These studies were performed at the
Sophia Children's Hospital (Rotterdam, The Netherlands). The study
protocol was approved by the institutional review board, and written
informed consent was obtained from the parents after the protocol had
been fully explained. The investigators were not responsible for the clinical care of the infants.
Lactate Kinetics
Glucose and lactate kinetics were quantified in ten normal infants of a size appropriate for their gestational age (AGA), six infants of IDDM mothers, and four SGA infants (Table 2). The mothers with IDDM were managed with multiple insulin doses per day or by continuous subcutaneous insulin infusion to maintain normoglycemia throughout the day. Their hemoglobin A1 concentrations at delivery were within the normal range. All infants were born at term gestation and had no intrapartum or neonatal problems. They had normal physical examinations and no apparent clinical problems. The tracer isotope infusions were started within 4-5 h after birth in eight normal AGA infants and three IDDM infants. Other infants were studied between 8 and 24 h after birth. Tracer infusion in the latter group was started 4-5 h after the last feed and continued for the next 4 h. [6,6-2H2]glucose [98 atom % excess (APE) 2H enrichment; Merck, Dorvall, QC, Canada] and [13C3]lactate (90 APE 13C; Merck) were each infused at a prime constant-rate infusion. For both [6,6-2H2]glucose and [13C3]lactate, the infusion rate was 30 µg · kg
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Analytical Methods
Plasma glucose was measured by the glucose oxidase method. Blood lactate levels were measured using lactate dehydrogenase. Deuterium enrichment of hydrogens on C-6 of glucose was measured as described previously (4, 22). Briefly, C-6 of glucose with its hydrogens, after preparatory isolation and purification, was cleaved by periodate oxidation to formaldehyde, which, when condensed with ammonium hydroxide, forms hexamethylenetetramine. The latter was analyzed on a gas chromatography-mass spectrometry (GC-MS) system (HP 5970 equipped with an HP 5890 gas chromatograph; Hewlett-Packard, Palo Alto, CA). The GC-MS conditions were as follows: a nonpolar cross-linked methyl siloxane capillary column (HP-1, Hewlett-Packard) was used. Its dimensions were 30 m in length, 0.25 mm ID, 0.25 µm film thickness, 220°C injection temperature, 105°C oven initial temperature for 5.6 min, final temperature 230°C, and 45°C/min ramp rate. The retention time for hexamethylenetetramine was ~4.2 min. Electron impact ionization (70 eV) was used, and ions of mass-to-charge ratios 140 and 141 were monitored using selective ion monitoring technique. Standard solutions of glucose of known enrichment were run along with those of unknown enrichment to calibrate for instrumental variations.The (m+6) enrichment of glucose (glucose m6, i.e., all carbons of glucose labeled with 13C) was measured using chemical ionization MS as described previously (1, 40). The (m+2) enrichment of glucose in [6,6-2H2]glucose was measured using a pentaacetate derivative, as previously described (23). The deuterium enrichment of glucose was corrected for the contribution of 13C from lactate. Plasma lactate enrichment was measured using an n-propylamide heptafluorobutyrate derivative (38). The 13C incorporation into glucose was estimated from the enrichment of C-1 of plasma glucose with the enzymatic decarboxylation method (21). 2H enrichment of total body water (plasma sample) was measured using the zinc reduction method on an isotope ratio mass spectrometer (Dr. W. Wong; Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX).
Calculations
The rates of appearance (Ra) of glucose and lactate were calculated from the dilution of tracer glucose in plasma, as described (39)
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The contribution of GNG from pyruvate was calculated as
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The enrichment in C-6 is multiplied by 0.5 because of two hydrogens on C-6. Total GNG is calculated by multiplying the fractional contribution of GNG with total glucose Ra.
The Ra of lactate was calculated using the tracer dilution equation, as in the first equation and in Ref. 39. The incorporation of lactate carbon into glucose was estimated by precursor-product relationship. The fraction of glucose from lactate equals the 13C/12C ratio of glucose C-1 divided by the 13C/12C ratio of plasma lactate. It was assumed that the 13C/12C ratio of glucose C-1 represents the enrichment of all carbons of glucose. No correction was made for the loss of tracer carbon via exchange in the tricarboxylic acid cycle and, therefore, the estimates of lactate C incorporation into glucose represent minimal estimates.
All data are reported as means ± SD. Group comparisons were made using parametric and nonparametric statistical methods with Statistix software (Analytical Software, La Jolla, CA).
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RESULTS |
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Gluconeogenesis via Pyruvate 2H2O Studies
Term infants. As displayed in Table 1, the term infants were appropriate for gestational age and were studied at a mean age of 46 h. They maintained normal plasma glucose concentration throughout the 8 h of fasting. The mean plasma glucose concentration was 68 mg/dl (3.8 mM).
The 2H enrichment of plasma water and that of hydrogens on C-6 of glucose are displayed in Table 3. Infant no. 6 had received a smaller dose of 2H2O due to spillage. Also displayed are the m6 enrichments of glucose and the calculated contribution of GNG via pyruvate. A steady-state isotopic enrichment was evident in all infants. The Ra of glucose as measured by [13C6]glucose tracer dilution ranged between 4.9 and 5.9 mg · kg
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Preterm babies.
The preterm infants were studied between days 3 and
4 after birth. As anticipated in this group, because of
clinical considerations, they were receiving a wide range of total
calories (64-143
kcal · kg1 · day
1). The
rate of exogenous glucose infusion (I) ranged between 3 and 10.6 mg · kg
1 · min
1 (16-59
µmol · kg
1 · min
1; Table
4). Their plasma glucose concentration
ranged between 4 and 7 mmol/l. Total Ra of glucose
quantified by [13C6]glucose tracer dilution
was 6-16
mg · kg
1 · min
1 (33-83
µmol · kg
1 · min
1),
and the rate of endogenous glucose production (Re) was
0-7 mg · kg
1 · min
1.
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Glucose and Lactate Kinetics
The plasma glucose and lactate levels were unchanged throughout the study period, and no significant difference was evident among normal infants, SGA infants, and infants of IDDM mothers (Table 5). The plasma C-peptide levels were slightly higher (P = nonsignificant) in the infants of diabetic mothers. The Ra of glucose was also similar in the three groups. The measured rates of glucose Ra when [6,6-2H2]glucose was used were slightly lower than those estimated using [13C6]glucose tracer. The reason for this difference remains undetermined (17). The estimated rate of plasma lactate turnover was 38 µmol · kg
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DISCUSSION |
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In the present study, we have documented for the first time that healthy full-term neonates establish GNG from lactate 4-6 h after birth, and that GNG from pyruvate contributes ~30% of total glucose release at ~5 h after the last feed. In preterm infants, even in the presence of exogenous glucose and other nutrient administration, GNG is a significant contributor to the total glucose turnover. These data are important for the nutritional management of sick newborns and contribute to our understanding of extrauterine adaptation of the human neonate.
Although GNG has been estimated indirectly in the human newborn by quantifying the glucose carbon recycling (8, 18), or in the SGA infants by estimating incorporation of alanine C into glucose (10), no data exist documenting the contribution of GNG or the appearance of GNG in the full-term healthy newborn infant. In the present study, using the method of deuterium labeling of body water, we have documented that, in the healthy newborn between 35 and 68 h after birth and 5 h after the last feed, GNG contributed ~30% to the total glucose Ra. These estimates are of a similar magnitude to those seen in normal healthy adults after an overnight fast (13, 37). The deuterium incorporation in the hydrogens of C-6 of glucose quantifies the contribution of pyruvate to glucose and does not include the contribution of glycerol (4, 27). In addition, because of a lack of complete equilibrium between deuterium in body water and methyl hydrogens (C-3) of pyruvate, the measurement of 2H enrichment on C-6 of glucose results in underestimation (by ~10%) of the contribution of GNG via pyruvate to total glucose Ra. The incorporation of 2H on C-5 of glucose, although more precise for the estimation of total GNG, is difficult to use in neonates because of the very large sample size requirements (3, 4).
These measurements of GNG via pyruvate are similar to the estimates of
glucose carbon recycling made by us in similar neonates with
[13C6]glucose (8). In that
study, the estimated glucose Ra from tracer dilution in
eleven healthy full-term infants after an 8- to 9-h fast was 28 µmol · kg1 · min
1, and
glucose C recycling amounted to 35% or 10.4 µmol · kg
1 · min
1.
Because glucose carbon recycling involves return of lactate and
pyruvate from the periphery back to the liver and their incorporation into glucose, estimation of glucose C recycling gives an estimation of
GNG via pyruvate. If the contribution of glycerol, ~4.5
µmol · kg
1 · min
1
(31, 35), is also included, then the total GNG in a
healthy newborn will amount to ~14
µmol · kg
1 · min
1, or
~46% of the total glucose Ra of 30 µmol · kg
1 · min
1. This
is significant and implies an important role of GNG in glucose
homeostasis even after a brief fast. The quantitative contribution of
various precursors to GNG via pyruvate remains undetermined.
The data in preterm babies, although variable, are also significant in that they underscore the quantitatively large contribution of GNG to glucose production, even when the endogenous rate of glucose production was low, e.g., infants infused with glucose plus amino acids with or without lipids. It is of interest that, in these babies also, GNG via pyruvate contributed 20-40% to endogenous production of glucose. In babies who were receiving glucose alone parenterally, the contribution of GNG was variable. It was highest (~50%) in the two infants (nos. 4 and 5) who were receiving intravenous glucose at the lowest rate. These measurements are of similar magnitude to those reported by Sunehag et al. (36) and Keshen et al. (25) in studies of low-birth-weight babies in which different isotopic tracer methods were used.
These data suggest that GNG should be considered as one of the several substrate cycles, like the triglyceride fatty acid cycle and protein turnover, which are active at all times and which can be rapidly accelerated at the time of acute demand.
Only one other study has quantified lactate turnover in the human
newborn. Cowett and Wolfe (7), using the
[13C3]lactate tracer dilution technique,
reported the rate of lactate turnover to be 77.2 ± 13.0 µmol · kg1 · min
1 in
full-term infants between 9 and 42 h after birth, and 100 ± 19.2 µmol · kg
1 · min
1 in
preterm infants. Their estimates are much higher than those reported in
the present study. The differences may be related to age of the
infants, intercurrent illness, or relationship to the last feed.
Whereas a majority of the infants in the present study were
investigated during the first few hours after birth (8/10 normal and
4/6 IDDM) and were not receiving any intravenous fluids or antibiotics,
such was not the case in the study of Cowett and Wolfe. Our data on
lactate turnover are similar to those reported in infants and children
aged 1-25 mo, which range between 25 and 44 µmol · kg
1 · min
1
(2), and they are much higher than those reported in
normal and diabetic adult subjects on the basis of similar tracer
methods (9). The calculated contribution of lactate to
glucose in our study, without account for loss of tracer in the
tricarboxylic acid cycle, was ~18%. Correction for the loss of
tracer (correction factor ~1.5) (14, 24) would yield
lactate's contribution to be ~27%, similar to that observed using
the 2H2O method.
Of interest, the Ra of lactate turnover was almost twofold the Ra of glucose turnover. This is in contrast to the data in adults, in which lactate turnover has been reported to be much lower than the rate of glucose turnover (in lactate equivalents) (5, 6, 9, 14, 24, 26, 28, 34). This would suggest either a rapid rate of equilibrium of the tracer between various compartments of lactate (plus pyruvate plus alanine) in babies or an influx of carbon into the lactate pool from nonglucose sources, e.g., amino acids. Such an hypothesis remains to be examined. The high rate of lactate turnover is also significant, because lactate has been suggested to be an important metabolic fuel for the brain in the newborn period (30). Finally, the lack of any significant difference among normal infants, SGA infants, and infants of IDDM mothers was not surprising. It essentially reflects the clinical practice of rigorous intrapartum regulation of maternal metabolism. Furthermore, because a large fraction of lactate C is derived from glucose, a difference in lactate kinetics will not be anticipated in the presence of similar rates of glucose turnover (41).
In summary, the present data show that GNG from lactate is apparent soon after birth in the healthy newborn infant and that it contributes ~30% of the total glucose produced. Significant contribution of GNG to glucose Ra could be observed in healthy babies within 5 hours of last feed and was also seen in preterm infants while they received parenteral glucose and other nutrients.
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ACKNOWLEDGEMENTS |
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We appreciate the assistance of the nursing staff of the General Clinical Research Center at MetroHealth Medical Center, the expert support of Alicia O'Brien and Ed Burkett, and the secretarial support of Joyce Nolan.
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FOOTNOTES |
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This work was financially supported by National Institutes of Health Grants HD-11089 and RR-00080.
Address for reprint requests and other correspondence: S. Kalhan, MetroHealth Medical Center, 2500 MetroHealth Dr., Cleveland, OH 44109-1998 (E-mail: sck{at}po.cwru.edu).
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.
Received 1 February 2001; accepted in final form 10 July 2001.
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