1 Exercise Physiology Laboratory, Department of Integrative Biology, University of California, Berkeley, California, 94720; 2 University of Colorado Health Sciences Center, Division of Cardiology, Denver, Colorado 80262; and 3 Geriatric Research, Education, and Clinical Center, Palo Alto Veterans Affairs Health Care System, Palo Alto, California 95304
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ABSTRACT |
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The hypothesis that
endurance training increases gluconeogenesis (GNG) during rest and
exercise was evaluated. We determined glucose turnover with
[6,6-2H]glucose and lactate incorporation into
glucose by use of [3-13C]lactate during 1 h of
cycle ergometry at two intensities [45 and 65% peak
O2 consumption
(O2 peak)]
before and after training [65% pretraining
O2 peak],
same absolute workload (ABT), and 65% posttraining
O2 peak, same
relative intensity (RLT). Nine males (178.1 ± 2.5 cm, 81.8 ± 3.3 kg, 27.4 ± 2.0 yr) trained for 9 wk on a cycle ergometer 5 times/wk for 1 h at 75%
O2 peak. The power
output that elicited 66.0 ± 1.1% of
O2 peak pretraining elicited 54.0 ± 1.7% posttraining. Rest and exercise arterial glucose concentrations were similar before and after training, regardless of exercise intensity. Arterial lactate concentration during
exercise was significantly greater than at rest before and after
training. Compared with 65% pretraining, arterial lactate concentration decreased at ABT (4.75 ± 0.4 mM, 65% pretraining; 2.78 ± 0.3 mM, ABT) and RLT (3.76 ± 0.46 mM) (P < 0.05). At
rest after training, the percentage of glucose rate of appearance
(Ra) from GNG more than doubled (1.98 ± 0.5%
pretraining; 5.45 ± 1.3% posttraining), as did the rate of GNG (0.11 ± 0.03 mg · kg
1 · min
1
pretraining, 0.24 ± 0.06 mg · kg
1 · min
1
posttraining). During exercise after training, %glucose Ra
from GNG increased significantly at ABT (2.3 ± 0.8% at 65% pre- vs. 7.6 ± 2.1% posttraining) and RLT (6.1 ± 1.5%), whereas GNG
increased almost threefold (P < 0.05) at ABT (0.24 ± 0.08 mg · kg
1 · min
1
65% pre-, and 0.71 ± 0.18 mg · kg
1 · min
1
posttraining) and RLT (0.75 ± 0.26 mg · kg
1 · min
1). We conclude that endurance
training increases gluconeogenesis twofold at rest and threefold during
exercise at given absolute and relative exercise intensities.
exertion; lactate; glucose; stable isotopes
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INTRODUCTION |
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IN LIGHT OF THE IMPORTANCE of maintaining blood glucose homeostasis during prolonged exercise, the effects of endurance training on gluconeogenesis (GNG) in exercising humans have received little attention. Results of previous investigations suggested that endurance training decreases (7) or does not change (23) GNG in humans during exercise at a given absolute intensity compared with before training. However, increased GNG has been reported in trained compared with untrained rats during hard exercise (10). Additionally, increased glucose carbon recycling in trained compared with untrained rats was reported during the last 30 min of a 60-min exercise bout that followed a 30-h fast to deplete liver glycogen stores (12). Furthermore, data from studies using isolated rat liver perfusion indicated that endurance training increases GNG capacity from lactate (11, 30) and alanine (28). Moreover, norepinephrine-stimulated GNG from lactate was increased in liver slices prepared from endurance-trained compared with untrained rats (25). Thus, in contrast to results of investigations on humans, the more extensive data from studies on rats strongly suggest that endurance training increases GNG capacity at rest as well as during exercise.
The purpose of the present investigation was to evaluate the hypothesis that endurance training increases GNG in men during exercise at given absolute and relative exercise intensities compared with that before training. For this purpose, we utilized a longitudinal design and studied men pre- and posttraining at exercise intensities known to alter circulating lactate concentration and splanchnic circulation.
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METHODS |
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Subjects
Nine healthy sedentary male subjects aged 19-33 yr were recruited from the University of California, Berkeley campus by posted notices. Subjects gave informed consent, were considered untrained if they engaged in no more than 2 h of physical activity per week for the previous year, and had a peak oxygen consumption (Experimental Design
After interviews and preliminary screening, subjects performed two graded exercise tests to determinePreliminary Testing
All exercise tests were performed on an electronically braked cycle ergometer (Monark Ergometric 829E). For determination ofDietary Protocol
On the night preceding each isotope trial, subjects were admitted to the metabolic ward, where they remained until testing was completed the following day. Subjects were fed a standardized dinner [1,174 kcal: 66% carbohydrate (CHO), 21% fat, 13% protein], which was replicated the night before each experimental trial. Later that evening, subjects ate a standardized snack (500 kcal: 53% CHO, 31% fat, and 16% protein) before retiring. Two subjects were tested per day, with morning and afternoon testing randomly assigned to each subject for the first trial and replicated for all subsequent trials. Morning procedures started at 7 AM, and preliminary afternoon procedures began at 1 PM. Morning subjects ate a standardized pretrial meal with a calculated low glycemic index (13) (448 kcal: 72% CHO, 10% fat, 18% protein) at 6 AM, 1 h before procedures started and 4.5-5 h before exercise. Afternoon subjects ate a standardized breakfast in the morning (729 kcal: 57% CHO, 33% fat, 10% protein) and the standardized pretrial meal at noon, again 1 h before procedures began and 4.5-5 h before exercise.Catheterizations
After local lidocaine anesthesia, the femoral artery was cannulated using standard percutaneous techniques, as previously described (4, 5). One subject experienced blood leaking from catheter placements during the beginning minutes of exercise at 65% pretraining and did not perform further exercise. As a result, a sample size of 8-9 was used for calculations and comparisons.Tracer Protocol
A venous catheter was placed in an antecubital vein on the morning of each trial for infusion of stable isotope solutions during 90 min of rest and 1 h of exercise. Background blood samples were collected after catheterization of the femoral artery and vein. Subjects then received a primed continuous infusion of [6,6-2H]glucose and [3-13C]lactate while resting semisupine for 90 min. Glucose (4) and lactate (3) kinetics are reported separately. The priming bolus was equal to 23 times the resting lactate infusion rate. Tracer glucose and lactate were infused via a pump (Intelligent 522, Kendall McGaw, Irvine, CA) at 2 and 2.5 mg/min at rest, and at 6 and 7.5 mg/min during exercise, respectively, at 45% pretrainingBlood Sampling
Arterial blood samples were drawn anaerobically over 5 s after 75 and 90 min of rest and at 5, 15, 30, 45, and 60 min of exercise. Blood samples for determination of glucose and lactate concentrations and isotopic enrichments were immediately transferred to tubes containing 8% perchloric acid and were shaken and placed on ice. Blood for determination of arterial plasma lactate concentration was immediately placed on ice. After the final blood sample at the end of exercise, samples were centrifuged at 3,000 g for 10 min, and the supernatant was transferred to storage tubes and frozen atMetabolite Analyses and Isotope Enrichments
Glucose concentrations were measured in duplicate using a hexokinase kit (Sigma, St. Louis, MO). Lactate concentration was measured in duplicate on plasma by use of the method of Gutmann and Wahlefeld (16) with lactate dehydrogenase. Glucose isotopic enrichment was measured by gas chromatography-mass spectrometry (GC-MS; GC model 5890 series II and MS model 5989A, Hewlett-Packard) of the pentaacetate derivative of mass-to-charge ratio (m/z) 332, indicative of the M1 glucose isotopomer as described previously (14). Lactate isotopic enrichment was measured by GC-MS of the N-propylamide heptafluorobutyrate derivative, as described previously (3).Training Protocol
Training was performed on stationary cycle ergometers 5 days/wk with workloads adjusted to elicit heart rates corresponding to 75% ofCalculations
%Glucose Ra from GNG.
The percentage of glucose Ra from GNG was calculated as
previously described by Huie et al. (19) in our laboratory. This approach was derived from that of Zilversmit et al. (34)
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GNG.
The rate of GNG was calculated as shown previously (19)
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Glucose kinetics. Glucose Ra values were calculated using equations defined by Steele and modified for use with stable isotopes (33), as previously described (4).
Statistical Analyses
Significance of differences among average arterial glucose and lactate concentrations determined during the last 30 min of exercise were analyzed using a one-factor ANOVA with repeated measures. Differences between training states for body fat, ![]() |
RESULTS |
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Subject Characteristics
Anthropometric data on subjects pre- and posttraining have been reported previously (4) but are repeated in Table 1. Subjects were weight stable throughout the study period.
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Glucose and Lactate Concentrations
Glucose concentrations were not different between training states at rest or during exercise at any intensity (Table 2). Resting arterial lactate concentrations were similar before and after training (Table 2). Under all exercise conditions, arterial lactate concentrations increased significantly above rest, and the increase was directly related to exercise intensity, both before and after training. Compared with 65% pretraining
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Glucose Ra
Glucose Ra was similar at rest before and after endurance training (Table 2). Compared with rest, glucose Ra increased during exercise regardless of training state or exercise intensity (P < 0.05). Glucose Ra scaled to exercise intensity before and after training. Compared with 65% pretrainingGNG
Arterial glucose enrichments from the M1 glucose isotopomer were stable over time throughout rest and exercise but varied due to exercise intensity and tracer infusion rate (Fig. 1). At rest, the percentage of glucose Ra from GNG increased 175% after endurance training (P < 0.05; Fig. 2A). However, within a training condition, the percentage of glucose Ra from GNG did not change during exercise compared with rest. Compared with 65% pretraining
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Before training, the estimated GNG rate did not increase during
exercise compared with rest (Fig. 2B). However, GNG increased 125% during rest after endurance training (Fig. 2B). After
training, GNG increased significantly during exercise compared with
rest, as well as when compared with exercise before training. Compared with that during the 65% pretraining
O2 peak
condition, after training GNG increased 300% during exercise under the
ABT and RLT conditions (Fig. 2B).
The rate of GNG during exercise relative to arterial lactate
concentration followed a saturation-type relationship both before and
after training but peaked at arterial lactate concentrations twice as
great after training (Fig. 3A).
Before training, GNG relative to whole body oxygen consumption
(O2) peaked at 45% pretraining
O2 peak and
tended to decrease with increasing exercise intensity (Fig.
3B). After training, GNG relative to
O2 appeared to plateau at
RLT.
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DISCUSSION |
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This investigation is the first to use a longitudinal design to evaluate effects of endurance training on GNG in men exercising at given absolute and relative intensities. Our results indicate that 4.5-5.5 h after a meal, endurance training doubles GNG at rest despite unchanged arterial lactate concentration. Similarly, during exercise after training at given absolute and relative intensities compared with before training, GNG triples despite significantly decreased arterial lactate concentration.
Training Adaptations
Our training program was successful in promoting significant metabolic adaptations (Table 1). During our 9-wk training program, subjects significantly increasedNutritional Controls
We fed subjects to be weight stable and rested them the day before experimentation. Furthermore, we fed standardized meals with low glycemic indexes 4.5-5.5 h before exercise studies. Those efforts produced stable blood glucose levels during exercise, suggesting that subjects commenced exercise with normal liver glycogen reserves. Thus observed effects on GNG are attributable to exercise intensity and endurance training and are not confounded by hypoglycemia during exercise.Table 3 shows values for GNG in the current
study compared with literature values in humans estimated by using the
lactate-to-glucose precursor-product relationship. Furthermore, Table 3
shows data from investigations using deuterated water and mass
isotopomer distribution analysis (MIDA) techniques that reveal the
effect of time since last eating on resting GNG in humans. In the
current study, preexercise meals dampened rates of GNG compared with
values reported after an overnight fast in humans by use of the
lactate-to-glucose precursor-product relationship (Table 3). Rates of
GNG increase with duration of fast, as shown by studies utilizing
deuterated water and MIDA techniques (Table 3). Thus attenuated rates
of GNG in the current study were to be expected given the nutritional controls imposed. Our data emphasize the importance of preexercise meals on regulation of GNG and implicate the increasingly important role of GNG for maintenance of blood glucose homeostasis as duration of
fasting progresses.
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GNG After Training
Our results indicate the percentages of glucose Ra from GNG (Fig. 2A) as well as rates of GNG (Fig. 2B) increased at rest after endurance exercise training. However, the relative contribution of GNG to glucose Ra was small, <10%. Only one previous study investigated GNG rates at rest before and after training in humans, and that study reported similar rates of [13C]bicarbonate incorporation into glucose before and after training (7). In contrast, after endurance training, resting whole body GNG increased as estimated from [14C]lactate incorporation into glucose in rats (10, 11). Furthermore, enhanced capacity for GNG from both lactate and alanine was found in liver preparations obtained from endurance-trained rats (24, 25, 28, 30). Thus, although few data on endurance-trained humans are available with which to compare our results, they are consistent with data obtained on rats, indicating increased GNG capacity after endurance training.In humans exercising at given power outputs, GNG after endurance
exercise training has been reported to decrease, as estimated from
[13C]bicarbonate incorporation into glucose
(7), or remain unchanged, as estimated from the difference between
lactate disappearance rate (Rd) and lactate oxidation
(Rox) (23). In rats, however, Donovan and Brooks (10)
reported increased GNG from lactate at high but not moderate exercise
intensities, as estimated from [14C]incorporation into glucose after
[14C]lactate infusion. Moreover, Donovan and
Sumida (12) reported significantly greater glucose
Ra during the last 30 min of a 1-h exercise bout at a given
workload in trained compared with untrained rats after a 30-h
glycogen-depleting fast, concomitant with an increased rate of glucose
recycling. Turcotte and Brooks (31) reported data
consistent with increased GNG after training when administration of
mercaptopicolinic acid, an inhibitor of phosphoenolpyruvate carboxykinase, abolished the enhanced ability of trained rats to
maintain blood glucose homeostasis during treadmill exercise at a given
absolute power output. Again, our present data obtained on men are
similar to results of studies on rats, as we found a threefold increase
in GNG (P < 0.05) at ABT compared with 65% pretraining
O2 peak (Fig.
2B). We previously reported that lactate metabolic clearance
rate (MCR) tended (P = 0.06) to increase at ABT after training
compared with 65% pretraining
O2 peak (3). Our
results indicate that the tendency for increased lactate MCR after
training may partly be due to enhanced GNG from lactate.
The current study is the first to investigate effects of
endurance training on GNG in humans during steady-state relative exercise intensities. GNG tripled at a given relative exercise intensity after endurance training (Fig. 2B). In contrast,
using a progressive exercise protocol, MacRae et al. (23) found no effect of training on lactate removal by GNG at relative
exercise intensities of 65 and 80%
O2 peak. We are unable
to explain the differences in results obtained in the two studies, but
we note that different exercise protocols (continuous vs. progressive) and methods of estimating GNG were employed (13C
incorporation into glucose after lactate infusion vs. difference between lactate Rd and oxidation rate). Possibly, the
method of MacRae et al. overestimated GNG, as it is known that in
addition to oxidation and GNG, lactate carbons label the bicarbonate,
protein, and glycogen pools (6).
The relationship between GNG and arterial lactate concentration
([lactate]a) (Fig. 3A) also differs
from that obtained by MacRae et al. (23). In contrast, the present
results are reminiscent of those obtained on laboratory rats (10). In
their study, MacRae et al. reported similar GNG for any given
O2 before and after training, whereas we found GNG increased after training during exercise at any given
O2
(Fig. 3B). Our results are similar to those of others who
reported increased GNG in rats exercising at high, but not moderate,
RLT values (10). The relationship between GNG and
O2, which plateaued
with increasing
O2 after training (Fig. 3B), was also reported by Donovan and Brooks
(10) in rats. Thus our data on effects of endurance training on GNG relative to
O2 are similar to
previous investigations that employed measurements during isotopic
steady state.
We previously reported similar whole body lactate turnover and active
muscle lactate production after training at RLT compared with 65%
pretraining O2 peak
despite dampened arterial lactate concentration (3). Increased MCR and
active muscle lactate uptake promoted dampened
[lactate]a concentrations at RLT compared with
before training. The current findings indicate that part of enhanced
lactate MCR after training at RLT (3) can be attributed to increased
GNG from lactate.
Mechanisms for Enhanced GNG
Several investigators reported unchanged enzymatic capacity for hepatic GNG after finding similar pyruvate carboxylase (19) and PEPCK activities (30) in livers from trained compared with untrained rats, and so the increased capacity for GNG we observed in men after training may be related to factors such as altered redox and adenine nucleotide energy charge (15). The present data do not allow us to identify the step or steps responsible for enhanced GNG between blood lactate and glucose production, but training effects on lactate transport across cell membranes, one or more steps in the gluconeogenic pathway, or effects on splanchnic blood flow could be involved. As well, the present results do not allow us to discriminate between training effects on liver or the kidneys. Similarly, we need to acknowledge that the glucose flux rates measured were the resultant of hepatic and renal functions that we could not distinguish.Increased GNG at ABT and RLT after training, compared with 65%
pretraining O2 peak,
occurred despite attenuated [lactate]a (Table
2). Because training increased
O2 peak, the workload at ABT after training was performed at a lower relative exercise intensity (54% posttraining
O2 peak).
Liver blood flow decreases in direct proportion to relative exercise
intensity (2). Therefore, greater hepatic blood flow may have enhanced
lactate delivery to the liver even with attenuated
[lactate]a concentration during ABT (Table 2),
which may partially explain enhanced GNG at ABT. However, an
explanation for enhanced GNG at RLT after training due to alterations
in hepatic blood flow is less clear. RLT was unchanged, suggesting
similar liver blood flow. However, increased blood volume after
endurance training may have promoted enhanced hepatic perfusion after
blood shunting to active muscles during exercise. Possibly, greater GNG
after endurance training may be due to similar or increased liver
lactate delivery as a result of increased hepatic blood flow at both
ABT and RLT compared with 65% pretraining
O2 peak.
Previous investigations reported a decrease in the apparent Michaelis-Menten constant (Km) for hepatic lactate GNG after endurance training in rats (9, 29). If true for humans, decreased apparent Km for lactate GNG may also help explain increased GNG observed in the present study despite decreased arterial lactate concentration.
We have previously reported unchanged arterial insulin concentration
and significantly decreased arterial glucagon concentration after
training at ABT and RLT compared with 65% pretraining
O2 peak (4). A
lower glucagon-to-insulin ratio after training appears contradictory to increased hepatic GNG. However, Podolin et al. (24)
reported that endurance training increased hepatic sensitivity to
several glucoregulatory hormones, including glucagon in rats. Thus
increased GNG after endurance exercise training observed in our study
may be partially attributed to enhanced hepatic sensitivity to
glucoregulatory hormones.
Limitations
We employed a dilution factor (Hetenyi, H; see Ref. 18) to correct for loss of label and crossing over in the tricarboxylic acid (TCA) cycle. Loss of label in the TCA cycle was originally reported by Weinmann et al. (32), later quantitated by Strisower et al. (27) by use of incubated liver slices, and further estimated in vivo in dogs and rats (18), followed by humans (8). However, use of a constant correction factor to estimate GNG over a wide range of stresses is likely flawed for several reasons. First, the methodology assumed that acetate is only metabolized in liver, a supposition that is possibly untrue (26). Second, the use of a fixed correction factor accounts only for loss of label from the oxaloacetate (OAA) pool and therefore assumes OAA to be the "true precursor pool" and last site of tracer dilution during GNG. However, we now know that the triose phosphate pool is the true GNG precursor pool and the last site of possible dilution during GNG (17). And finally, H factors are species, nutrition, and (possibly) training state specific; therefore, use of a constant to correct for isotopic dilution during GNG in a metabolic environment different from that in which the constant was created will likely promote errors in computation.In resting subjects our data probably underestimated total GNG, as contributions from glycerol are not included in the correction factor we used. Furthermore, our exercise data underestimated GNG because we did not use a correction factor, assuming lactate to be the predominant GNG precursor and no dilution of the precursor pool (1). Thus, although absolute rates of GNG may be inexact, our data are interpretable with respect to the literature because our methodology is similar to that employed by others to study GNG during exercise (10, 19). Moreover, we used identical correction factors before and after training and therefore assumed that endurance training does not affect OAA dilution and loss of label from the TCA cycle. Our data will inaccurately estimate GNG to the extent that endurance training alters hepatic OAA dilution and loss of label. However, from a qualitative standpoint, we are confident of our interpretation that endurance training increases GNG during exercise, because our conclusion is based on uncorrected (H = 1) data.
In our report we have made repeated conclusions regarding training effects on hepatic GNG. However, kidneys are the other important site of GNG and have been shown to increase GNG capacity after endurance training (22). Thus, although most enhanced GNG after training likely came from the liver, lactate GNG in kidneys contributed as well.
Conclusions
Data from the secondary labeling of blood glucose from infused carbon-tracer lactate support the conclusion that 9 wk of endurance training increased GNG twofold at rest and threefold during exercise at given absolute and relative exercise intensities. Additionally, increased GNG during exercise at ABT and RLT after endurance training promotes increased lactate MCR and dampens arterial lactate concentrations compared with the untrained state. After training, the capacity for GNG was enhanced in men, even though the circulation concentration of lactate, the main gluconeogenic precursor, was reduced. ![]() |
ACKNOWLEDGEMENTS |
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We thank the subjects for participating in our study and complying with the training program. The assistance of the nursing staff and dietitians at the Geriatric Research, Education, and Clinical Center (GRECC) in the Palo Alto Veterans Affairs (VA) Health Care System is appreciated. We also thank David Guido for performing muscle biopsies and Jacinda Mawson for blood gas analysis. We thank the student trainers who were vital in subject training and transport. We greatly appreciate the help of Barry Braun and Shannon Dominick in blood sampling during the VA trials. Special thanks are extended to Lou Tomimatsu, Department of Clinical Pharmacology, UCSF, for preparation of tracer cocktails.
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FOOTNOTES |
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This work was supported by National Institutes of Health Grants DK-19577 and AR-42906.
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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: G. A. Brooks, Exercise Physiology Laboratory, Department of Integrative Biology, 5101 Valley Life Sciences Bldg., University of California, Berkeley, Berkeley, CA 94720-3140 (E-mail:gbrooks{at}socrates.berkeley.edu).
Received 14 May 1999; accepted in final form 24 September 1999.
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