1 Department of Integrative
Biology, We evaluated the
hypotheses that alterations in glucose disposal rate
(Rd) due to endurance training
are the result of changed net glucose uptake by active muscle and that
blood glucose is shunted to working muscle during exercise requiring
high relative power output. We studied leg net glucose uptake during 1 h of cycle ergometry at two intensities before training [45 and
65% of peak rate of oxygen consumption
(
exertion; glycogen; lactate; stable isotopes; crossover
concept
GLUCOSE DISPOSAL during exercise is dependent on power
output and muscle mass recruited (31). Chronic endurance exercise training decreases glucose flux at a given absolute power output as
observed first in rats (4) and reconfirmed in men (8, 14, 25) and women
(13). However, it is unclear that active muscle is responsible for
decreased whole body glucose uptake during given power outputs after
training (16, 35, 36). Several studies reported unchanged leg net
glucose uptake in trained compared with untrained subjects during 1 h
of exercise by use of mass balance in humans (16, 36) and a
nonmetabolizable glucose analog in rats (35). Only one study (30)
reported significantly decreased net glucose uptake throughout exercise in humans after training. Others reported decreased net glucose uptake
only during the 60th min of exercise (20) or a significant decrease at
10 min, with no further difference between trained and untrained
subjects for the remaining 2 h of exercise (22). Despite increased
GLUT-4 content in trained muscle (31) and increased insulin action
after training (9), tracer-measured glucose disposal rate
(Rd) is consistently decreased
throughout exercise after endurance training (8, 14, 25). Thus there are inconsistencies between results obtained by systemic tracers and
limb mass balance techniques, leaving open the role of noncontracting tissues in determining glucose flux during exercise.
In the absence of a study to determine the effects of exercise
intensity and endurance training on the relationships among working
muscle (exercising limb) net glucose uptake and whole body glucose
kinetics, we undertook a longitudinal study on nine young men.
Specifically, we sought to evaluate the hypothesis that alterations in
active muscle glucose uptake with training determine the changes in
whole body glucose kinetics. In addition, we sought to test the
hypothesis that glycemia is maintained during exercise after training
by a mechanism that shunts blood glucose from "inactive tissue,"
thereby sparing glucose for working muscle (3).
Subjects
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
O2 peak)] and
after training [65% pretraining
O2 peak, same
absolute workload (ABT), and 65% posttraining
O2 peak, same
relative workload (RLT)]. Nine male subjects (178.1 ± 2.5 cm,
81.8 ± 3.3 kg, 27.4 ± 2.0 yr) were tested before and after 9 wk
of cycle ergometer training, five times a week at 75%
O2 peak. The power
output that elicited 66.0 ± 1.1% of
O2 peak before
training elicited 54.0 ± 1.7% after training. Whole body glucose
Rd decreased posttraining at ABT
(5.45 ± 0.31 mg · kg
1 · min
1
at 65% pretraining to 4.36 ± 0.44 mg · kg
1 · min
1)
but not at RLT (5.94 ± 0.47 mg · kg
1 · min
1).
Net glucose uptake was attenuated posttraining at ABT (1.87 ± 0.42 mmol/min at 65% pretraining and 0.54 ± 0.33 mmol/min) but not at
RLT (2.25 ± 0.81 mmol/min). The decrease in leg net
glucose uptake at ABT was of similar magnitude as the drop in glucose Rd and thus could explain dampened
glucose flux after training. Glycogen degradation also decreased
posttraining at ABT but not RLT. Leg net glucose uptake accounted for
61% of blood glucose flux before training and 81% after training at
the same relative (65%
O2 peak) workload and
only 38% after training at ABT. We conclude that
1) alterations in active muscle
glucose uptake with training determine changes in whole body glucose
kinetics; 2) muscle glucose uptake
decreases for a given, moderate intensity task after training; and
3) hard exercise (65%
O2 peak) promotes a
glucose shunt from inactive tissues to active muscle.
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
O2 max) of <45 ml · kg
1 · min
1.
Subjects were included in the study if they had <25% percent body
fat, were nonsmokers, were diet and weight stable, had a 1-s forced
expiratory volume (FEV1) of 70%
or more of vital capacity, and were injury and disease free as
determined by physical examination. This study was approved by the
Committee for the Protection of Human Subjects at Stanford University
and the University of California, Berkeley (CPHS 97-6-34).
Experimental Design
After interviews and preliminary screening, subjects performed two graded exercise tests to determine the peak rate of oxygen consumption (Preliminary Testing
All exercise tests were performed on an electronically braked cycle ergometer (Monark Ergometric 829E). For determination ofTesting Protocol
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, 21% fat, 13% protein), which was replicated the night before each experimental trial. Later that evening, subjects ate a standardized snack (500 kcal: 53% carbohydrate, 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, whereas preliminary afternoon procedures began at 1 PM. Morning subjects ate a standardized pretrial meal with a calculated low glycemic index (11) (448 kcal: 72% carbohydrate, 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% carbohydrate, 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 and vein of the same leg were cannulated with standard percutaneous techniques as previously described (38). A 5.1-Fr, 50-cm, Cordis arterial flush catheter was inserted 25 cm and positioned in the distal abdominal aorta via the femoral artery. A 6-Fr thermodilution venous catheter (model 93-135-6F, American Edwards Laboratories) was placed with the tip in the distal iliac vein through a venous sheath in the femoral vein 20 cm from the skin. Both catheters were sutured to the skin and further secured by an Ace bandage wrap. The external portions of each catheter were directed toward the hip for easy access during exercise. Alternate legs were used for the two trials during both pretraining and posttraining testing. One subject experienced blood leaking from catheter placements during the beginning minutes of exercise at 65% pretraining and did not perform further exercise. Two different subjects did not receive a venous catheter for one of their trials. As a result, a sample size of 6-9 was used for calculations and comparisons.Tracer Protocol
A venous catheter was placed in an antecubital vein the morning of each trial for isotope infusion during 90 min of rest and 1 h of exercise. Background blood and breath 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. Lactate kinetics are to be reported separately. The priming bolus was equal to 125 times the resting glucose infusion rate. [6,6-2H]glucose was infused via an Intelligent pump 522 (Kendall McGaw, Irvine, California) at 2 mg/min at rest, 6 mg/min during exercise at 45% pretrainingMuscle Biopsy and Analysis
Immediately after the start of the isotope infusion, one vastus lateralis muscle was prepared for percutaneous needle biopsy. For each experimental trial, biopsies were taken from two locations separated by 1.5 cm: the distal site for preexercise sampling and the proximal site for immediate postexercise sampling. Right and left vastus lateralis muscles were alternated between trials. Biopsies taken at rest and within 10 s of exercise cessation were immediately plunged into liquid nitrogen and subsequently stored under liquid nitrogen and shipped on dry ice. Samples were analyzed for glycogen content as previously described (24).Blood Sampling
Blood temperature was obtained from a thermistor at the end of the venous thermodilution catheter immediately before blood sampling. Arterial and venous blood samples were drawn simultaneously and anaerobically over 5 s after 75 and 90 min of rest and at 5, 15, 30, 45, and 60 min of exercise. PO2, PCO2, and pH were measured within 30 min of blood sampling (ABL 300, Radiometer, Copenhagen, Denmark). Blood for determination of glucose and lactate concentration and glucose enrichment was immediately transferred to tubes containing 5% perchloric acid, shaken, and placed on ice. Arterial blood for hormone analysis was mixed with aprotinin, shaken, and 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 atHemodynamics
Heart rate and electrocardiogram (ECG) were continuously recorded and displayed with a three-lead ECG connected to a MacLab analog-to-digital converter (ADInstruments, Castle Hill, Australia) and tracked on a Macintosh 7200/200 Power Mac computer (Apple Computer, Cupertino, CA). Arterial blood pressure was also continuously recorded and displayed with a Transpac pressure transducer (Baxter) positioned at the level of the heart connected to the MacLab system and calibrated before every trial. Iliac venous blood flow was determined by thermodilution technique with a cardiac output computer (model 9520, American Edwards Laboratories) with a 10-ml bolus injection of sterile saline cooled to 0°C via an ice slurry (American Edwards Laboratories-Set II, 93-520). Measurements were made in triplicate or quadruplicate during rest and exercise immediately after blood sampling. The validity and precautions associated with this technique have been described previously (2).Metabolite Analyses and Isotope Enrichment
Glucose concentration was measured in duplicate with a hexokinase enzymatic kit from Sigma Chemical (St. Louis, MO). Lactate concentration was measured in duplicate with the method of Gutmann and Wahlefeld (15) with lactate dehydrogenase. Glucose isotopic enrichment was measured with the use of gas chromatography-mass spectrometry (GC model 5890 series II and MS model 5989A, Hewlett-Packard) of the pentaacetate derivative as described previously (13).Training Protocol
All training was performed on stationary cycle ergometers 5 days/wk with workloads adjusted to elicit heart rates, which were recorded daily, corresponding to the required intensity on the basis of maximal exercise test results. Subjects were asked to exercise 1 day/wk on their own in addition to cycle ergometry training so that total training was 6 days/wk. All subjects were exercising at 75% of theirCalculations
Leg respiratory quotient. Leg respiratory quotient (RQ) was calculated from the ratio of venous-arterial CO2 difference (v-aCO2) and arteriovenous O2 difference (a-vO2).
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Blood CO2 content. Blood PCO2, PO2, pH, and hemoglobin (Hb) were measured on both arterial and venous samples and used in the calculations by Douglas et al. (10) for determination of blood CO2 content, estimating CO2 solubility and apparent dissociation constant from the equations of Kelman (21).
Blood O2 content. Blood O2 content was calculated with hemoglobin concentration, and saturation (SO2) was determined from an equation from Nunn (26).
O2 of
the legs.
Leg O2 was calculated with the
Fick equation as follows
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Whole body and leg carbohydrate oxidation.
Total carbohydrate oxidation for both whole body [from
respiratory exchange ratio (RER)] and exercising leg (from leg
RQ) were determined from stoichiometric equations (12), assuming a
whole body nitrogen excretion rate of 135 g · kg1 · min
1
(7).
Glucose kinetics. Glucose rate of appearance (Ra), glucose disposal rate (Rd), and metabolic clearance rate (MCR) were calculated with equations defined by Steele and modified for use with stable isotopes (37).
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Net metabolite exchange. Net metabolite exchange differences were calculated from the product of leg blood flow and arteriovenous differences where arterial and venous (superscripts a and v) hematocrit (Hct) values were used to correct for changes in plasma volume
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Hormones. Radioimmunoassays were performed to determine plasma concentrations of insulin (INCSTAR, Stillwater, MN) and glucagon (Diagnostic Products, Los Angeles, CA). The values reported on resting and exercising subjects are those that correspond in time to when glucose flux rates were calculated.
Statistical Analyses
Significance of differences among mean arterial glucose and lactate concentrations from the last 30 min of exercise were analyzed with a one-factor ANOVA with repeated measures. Differences between groups and changes over time in RER, RQ, inactive tissue RQ, single leg blood flow, glucose arteriovenous difference, net uptake of glucose, glucose Ra and Rd, glucose MCR, and arterial enrichment were determined with a repeated-measures factorial ANOVA. Post hoc comparisons were made with Fisher's protected least significant difference test. One-hour averages of insulin and glucagon concentrations, leg and whole body carbohydrate oxidation, percentage of glucose Rd accounted for by net glucose uptake, and glycogen degradation were analyzed with paired Student t-tests. Statistical significance was set at ![]() |
RESULTS |
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Subject Characteristics
Anthropometric data for subjects pre- and posttraining are shown in Table 1. Subjects were weight stable throughout the study period, although percent body fat decreased significantly as determined by both skinfold measurements (
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Muscle Glycogen Concentrations
Resting muscle glycogen concentration was significantly increased 46% after training and decreased during exercise at all intensities (Table 2). Endurance training attenuated muscle glycogen degradation at the same absolute power output (P < 0.05) by 33%. There were no differences in muscle glycogen degradation at RLT posttraining.
|
Insulin and Glucagon Concentrations
Resting arterial insulin concentration decreased (P < 0.05) 33% after training (Fig. 1A). Insulin concentrations during the last 30 min of exercise were decreased 46 and 69% at 45% pretraining and 65% pretraining, respectively, and 36 and 38% at ABT and RLT, respectively (Fig. 1A). Pretraining, insulin concentration significantly decreased at 65%
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RER, Leg, and Inactive Tissue RQ
RERs during exercise were significantly increased at 65% pretraining (0.96 ± 0.01) compared with 45% pretraining (0.93 ± 0.01; Ref. 2). When subjects were retested after training at ABT, there was a significant decrease in RER (0.93 ± 0.01 at ABT). There were no differences in RER values when subjects were tested at the same relative exercise intensity after training (0.95 ± 0.01 at RLT). Leg RQ was not significantly different at rest before or after training. During exercise, leg RQ significantly increased from 45% (0.89 ± 0.05) to 65% pretraining (0.98 ± 0.02). There was no difference in leg RQ at ABT (0.98 ± 0.03) or RLT (1.01 ± 0.02) posttraining. From the difference between leg RQ and whole body RER, an RQ for the remainder of the body was calculated. Inactive tissue RQ increased with elevated exercise intensity before training (0.89 ± 0.04 at 45% and 0.98 ± 0.04 at 65%Glucose Kinetics
Our isotope infusion protocol was successful in promoting similar stable blood glucose enrichments despite different metabolic infusion rates pre- and posttraining (Fig. 2). Resting glucose Ra and Rd were not changed by training, and flux rates scaled to exercise intensity both before and after training (Figs. 3, A and B). After training, whole body glucose Ra and Rd decreased 23 and 20%, respectively, at ABT but were not significantly different at RLT (Fig. 3, A and B). There was no effect of training on resting glucose MCR, but glucose MCR increased in the transition from rest to exercise under all conditions and scaled to exercise intensity before and after training (Fig. 3C).
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Arterial Glucose Concentration and Net Uptake by the Legs
Rest and exercise arterial glucose concentrations were similar before and after training, regardless of exercise intensity (Fig. 4A). Glucose arteriovenous differences were not different between training states at rest or during exercise before training (Fig. 4B). However, posttraining glucose arteriovenous differences were significantly (P < 0.05) lower at ABT compared with RLT and 65% pretraining (Fig. 4B). Expressed as a percentage of total vascular delivery, glucose fractional extraction during exercise was not significantly different between the two pretraining exercise intensities (2.3 ± 0.82% for 45% pretraining and 3.8 ± 0.75% for 65% pretraining; Fig. 4C). After training, fractional extraction of glucose for the hour of exercise was decreased at ABT (0.91 ± 0.60%) but not RLT (3.7 ± 1.2%) compared with before training (Fig. 4C). Single leg blood flow was not different at rest between training states, and blood flow scaled to exercise intensity, before and after training (Fig. 4D). Leg blood flow was significantly (P < 0.05) greater at ABT compared with 65%
|
Figure 5 displays the relationship between
exercise intensity and the relative role played by exercising legs in
removing blood glucose. At rest, leg net glucose uptake accounted for
24% of blood glucose Rd
pretraining and 19% posttraining. For a given power output, the
percentage of glucose Rd accounted
for by the legs tended to fall from 61% at 65% pretraining to 38% at
ABT. However, at RLT, our data indicate the legs accounted for most (81%) of glucose Rd.
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One-hour averages of leg carbohydrate oxidation calculated from leg RQ
and whole body carbohydrate oxidation calculated from pulmonary RER are
shown in Fig. 6. There was a significant
increase in leg carbohydrate oxidation at 65% pretraining compared
with 45% pre- and posttraining at RLT compared with ABT (Fig.
6A). Leg carbohydrate oxidation was
not different after training at ABT but significantly increased at RLT.
Whole body carbohydrate oxidation was significantly increased at 65%
pretraining compared with 45% pretraining and ABT intensities (Fig.
6B). There were no differences
between whole body carbohydrate oxidation at the same relative
intensity before and after training. Net glucose uptake during exercise
was unchanged before and after training with increased exercise
intensity (Fig. 6C). Net glucose
uptake during exercise was decreased after training at ABT and
unchanged at RLT compared with before training. Glycogen degradation
was enhanced pretraining but not posttraining with increased exercise intensity (Fig. 6D). Glycogen
degradation was attenuated posttraining at ABT but not RLT. Glucose
Rd is displayed in millimoles per minute to facilitate comparison between other measures of carbohydrate metabolism (Fig. 6E). The summation
of glycogen degradation and net glucose uptake, after subtraction of a
fraction of each corresponding to net lactate release (Fig.
6F), is similar to leg carbohydrate oxidation values from Fig. 6A. Thus
two independent methods (calorimetry and mass balance) reveal similar
leg carbohydrate oxidation rates.
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DISCUSSION |
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Our data on active limb glucose uptake and whole body glucose disposal,
as well as working limb RQ and RQ derived for the remainder of the
body, show that glucose uptake by active muscle dominates blood glucose
flux during hard (65%
O2 peak) exercise. If
anything, sparing of glucose uptake by metabolically inactive tissues
and "shunting" of blood glucose to active muscles appear to be
exaggerated during hard exercise after training. Additionally, we found
decreased net glucose uptake at the same absolute power output after
training, which could explain the reduction in whole body glucose
Rd observed (Figs.
3B and 6). In the aggregate, our data
derived from a variety of technical approaches show that glucose and
other carbohydrate-derived fuels predominate in active muscle, both
before and after endurance training.
Training Adaptations
Our training program was successful in promoting significant metabolic adaptations (Tables 1 and 2; Fig. 1A). During our 9-wk training program, subjects significantly increasedNutritional Controls
Our experiments were designed to reveal the effects of exercise and training on substrate utilization. We employed experimental and nutritional controls appropriate to represent practices and conditions typical in the population at large. For these reasons, we fed subjects to be weight stable and rested them the day before experimentation. Furthermore, we fed them standardized meals with calculated low glycemic index 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 the effects on substrate utilization we observed are attributable to exercise intensity and endurance training and are not confounded by undernutrition, liver glycogen depletion, or hypoglycemia.Limb Net Glucose Uptake
Pre- and posttraining values for leg net glucose uptake at rest (0.35 ± 0.28 mmol/min pretraining and 0.26 ± 0.06 mmol/min posttraining) were similar to literature values (1, 16, 19, 20, 22, 27, 29, 32, 36), which range from 0.15 ± 0.03 mmol/min (32) to 0.22 ± 0.03 mmol/min (1). The magnitude of pre- and posttraining exercise net glucose uptakes was also similar to literature values (1, 16, 19, 20, 27, 29). However, regarding the effects of training, our data are similar to some (20, 30) but not others (16, 33). We found decreased leg net glucose uptake for a given absolute power output after training (Figs. 4E and 6). Henriksson (16) and Saltin et al. (33), however, reported unchanged leg net glucose uptake after training during leg cycle ergometry at the same absolute intensity. Our results may differ from others due to type of training (one-legged in Saltin et al., two-legged in present study), length of training (4 wk in Saltin et al., 9 wk in present study), and nutritional state [12- to 14-h fast in Henriksson (16), 4.5- to 5.5-h fast in present study]. Our data are similar to those of Jansson and Kaijser (20) and Richter et al. (30) who reported decreased leg net glucose uptake during exercise at the same absolute intensity after training. Thus changes in leg net glucose uptake due to endurance training (i.e., decreased net glucose uptake at ABT with no change at RLT compared with pretraining) are similar to alterations in whole body glucose flux (see Whole Body Glucose Disposal ...).Dampened active muscle glucose uptake is often assumed to cause decreased glucose Rd at ABT after endurance training (8, 25). However, we are the first to measure net glucose uptake and glucose turnover at absolute and relative exercise intensities to provide evidence that changes in active muscle glucose uptake can explain altered whole body Rd. After training, working muscle glucose uptake at ABT decreased sufficiently to attenuate whole body glucose turnover (Fig. 6). Thus, even though glucose turnover is a whole body measure, our data suggest it is appropriate to explain dampened glucose turnover by decreased working muscle glucose uptake. However, our data do not rule out the possibility that decreased inactive tissue carbohydrate oxidation may also contribute to dampened glucose Rd.
It is feasible to consider the possibility that attenuated glucose uptake in inactive tissues contributes to decreased whole body glucose Rd during given power outputs after training. As determined from the difference between whole body RER and leg RQ, inactive tissue RQ decreased during exercise after training. However, interpretation of RQ measurements in terms of glucose sparing is limited because of the inability to determine sources of carbohydrate oxidized. For instance, after training arterial lactate concentration was lower, and so decreased lactate uptake and oxidation by inactive tissues could have explained the lower RQ. Furthermore, on the basis of observations of unchanged or slightly increased plasma insulin concentrations during exercise after training (Fig. 1A) and constant blood glucose concentration (Fig. 4A), it is unlikely that blood glucose uptake decreased in inactive tissue at ABT. More likely, decreased inactive tissue carbohydrate oxidation may be due to reduced glycogenolysis in inactive muscle (1), potentially due to dampened catecholamine concentrations (5). Regardless of the explanation for a decrease in carbohydrate oxidation by inactive tissues during leg cycling after training, our data indicate that inactive tissue carbohydrate oxidation is small in comparison with total body carbohydrate oxidation during exercise. Therefore, the component of glucose Rd attributable to inactive tissue is not likely to have had major effects on blood glucose kinetics (Fig. 6).
Given adaptations to training that appear to increase glucose
utilization, such as increased GLUT-4 content and hexokinase activity
(5, 30), an explanation for decreased leg net glucose uptake for a
given power output after training is not apparent. It is possible,
however, that increased GLUT-4 content after endurance training is more
important during recovery after exercise, to maximize glycogen stores
in preparation for the next exercise bout. Negative correlations
between leg net glucose uptake and insulin concentration
(r = 0.75) and between glucose
uptake and insulin-to-glucagon ratio
(r =
0.73) (Figs.
1A,
1C,
4C, and 6) suggest insulin is not
likely to be a major determinant of leg net glucose uptake in working
muscle. Because endurance training increases insulin sensitivity (9),
decreased leg net glucose uptake at ABT with unchanged or slightly
increased insulin concentration (Fig.
1A) suggests that
insulin-independent mechanisms determine working muscle glucose uptake.
Possibly, factors such as decreased GLUT-4 translocation to the
sarcolemma (30), decreased malonyl-CoA concentration or carnitine
palmitoyltranferase 1 affinity for malonyl-CoA (23), or
increased lactate uptake (30) are more influential than circulating
insulin concentration in dampening leg glucose uptake during exercise
at a given power output after training.
Whole Body Glucose Disposal and Leg Net Glucose Uptake
Our results of whole body glucose turnover are similar to others who have found decreased glucose Ra and Rd at the same absolute (8, 14, 25) but not the same relative exercise intensity (14) after endurance exercise training. Our results are also consistent with the idea that relative exercise intensity is a main determinant of glucose turnover (6), because there were no differences in glucose turnover at the same percentage ofEven though glucose Rd (and net
glucose uptake, as we have shown) scale to relative exercise intensity
before and after training, the gain in glucose disposal is low compared
with the gain in overall metabolic rate and carbohydrate oxidation
during exercise. For instance, before training, exercise at 65%
O2 peak elicited a
sevenfold increase in
O2
and an eightfold increase in total carbohydrate oxidation compared with
rest. Under this condition, glucose
Rd doubled. After training,
exercise at 65%
O2 peak elicited eight-
and ninefold increases in
O2
and total carbohydrate oxidation, respectively, compared with rest.
Again, glucose Rd little more than
doubled during exercise compared with rest. Thus it is clear that
although blood glucose flux and oxidation scale to exercise intensity,
both before and after training, other carbohydrates are relatively more
important as energy sources.
Sparing of glucose uptake by inactive tissues and
redirection of hepatic glucose production to working legs during leg
cycling exercise were not apparent at moderate power outputs. Leg
glucose uptake accounted for only 48% of blood glucose
Rd at 45%
O2 peak before training
and 38% at ABT after training. The decline in the percentage of
glucose Rd accounted for by net
glucose uptake from 61% at 65% pretraining to 38% at ABT was
impressive because one leg blood flow increased significantly from 5.2 ± 0.3 to 5.8 ± 0.2 l/min at ABT (Fig.
4D; Ref. 2). Thus the decline in leg net glucose uptake for a given absolute exercise power output after
training (Fig. 4E) was the result of
decreased glucose extraction (Fig.
4C) not altered vascular conductance.
Under some conditions, increased blood flow from insulin-stimulated nitric oxide release (34) may enhance glucose uptake. However, we observed that during exercise after training leg net glucose uptake decreased at ABT (Fig. 4E) despite significantly greater leg blood flow (Fig. 4D). Moreover, the observations of unchanged and low arterial insulin concentrations during exercise at ABT compared with 65% pretraining (Fig. 1A) are interpreted to suggest that elevated blood flow during ABT after training was not likely due to insulin-stimulated nitric oxide release. Consistent with our observations, Pendergrass et al. (28) reported that elevated blood flow from insulin-like growth factor I infusion did not increase skeletal muscle glucose uptake. Thus it appears that decreased muscle glucose uptake at a given power output after training cannot be ascribed to alterations in blood flow. Our data are consistent with an intramuscular effect of training (e.g., decreased GLUT-4 translocation) reducing muscle glucose uptake during exercise at a given, moderate intensity power output (30).
Our data support the concept of glucose shunting to active muscles at
high relative power outputs both before and after training (Fig. 5). At
the same relative intensity (65%
O2 peak), leg net
glucose uptake accounted for 61% of blood glucose
Rd pretraining, which increased to
81% after training (Fig. 5). Posttraining, the new exercise power
output during RLT was 16% (25 W) greater than during the pretraining
65%
O2 peak task, and
limb blood flow increased 20% to 7.0 ± 0.3 l/min, while net
glucose uptake was unchanged compared with 65% pretraining. Thus, when
viewed from the perspective of relative power output, after training the working limb appears to respond essentially as before training.
Glycogen Degradation
Consistent with results of others (20, 22, 33, 36), our training program resulted in attenuated muscle glycogen degradation at the same absolute power output as before training (Table 2; Fig. 6). Henriksson (16) reported average glycogen degradation rates for 1 h of exercise at 0.82 µmol · g wet wtWe do not know of any other report that compared muscle glycogen
degradation rates at a given relative exercise intensity before and
after training. Most investigations analyzed muscle glycogen
degradation at the same absolute power output as before training.
However, Hultman and Spriet (17) compiled data from many training
studies and plotted glycogen degradation rates during exercise relative
to work intensity performed
(O2 max). The exponential relationship suggested similar rates of glycogen
degradation between subjects of different athletic histories at a given
percentage of maximal effort, supporting relative exercise intensity as
a critical factor determining rate of glycogen degradation (Table 2;
Fig. 6) (17). Thus our investigation is the first to provide data with
muscle biopsies showing that rates of glycogen degradation are
equivalent in the trained and untrained state when exercise is
performed at similar relative intensities.
In the present and companion report (2), we provided data on the effects of exercise and training on limb and whole body substrate utilization; those data were obtained with diverse technologies, each with inherent and unique assumptions and limitations. Results of working limb muscle glycogen degradation (Fig. 6D) and leg net glucose uptake (Fig. 6E) when summed and corrected for net lactate release (Fig. 6F) show remarkable consistency to data derived from leg RQ (Fig. 6A) and whole body RER (Fig. 6B). The aggregated data provide a consistent picture showing preferential use of carbohydrate-derived fuels at high relative power output regardless of training state.
In conclusion, whether data were obtained by pulmonary indirect
calorimetry, measurements of arteriovenous differences of glucose,
CO2 and
O2, isotope tracers, or muscle
biopsies, the results of the present study (Fig. 6) show that high
power output exercise depends on carbohydrate-derived fuel sources
regardless of training state. Thus relative exercise intensity emerges
as a major predictor of substrate utilization pattern. Leg net glucose uptake, glycogenolysis, and whole body glucose
Rd decrease for a given submaximal
power output after training. Because changes were accomplished in an
environment of unchanged circulating insulin concentration,
intracellular signals must be responsible for the training effect,
rendering working muscle less sensitive to insulin during moderate
intensity exercise. Results of the present study support the concept
that blood glucose is shunted from inactive tissues to
active muscle during hard (65%
O2 peak) exercise, regardless of training state. Additionally, our data indicate that
decreased working muscle glucose uptake at a given absolute power
output posttraining explains attenuated whole body glucose Rd. Although blood glucose may be
directed to working muscle during exercise involving recruitment of a
large fraction of total body muscle mass, the gain in net glucose
uptake by working muscle during hard exercise is small compared with
the gain in total body carbohydrate oxidation. Thus the apparent
sparing of glucose uptake by inactive tissues and the low gain in
muscle glucose uptake in response to gradations in power output are
viewed as the means to maintain glycemia during hard exercise, which
requires high rates of carbohydrate oxidation.
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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 in the Palo Alto Veterans Affairs 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 Domineck in blood sampling during the Veterans Affairs trials.
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FOOTNOTES |
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This work was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant AR-42906 and National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-19577.
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: G. A. Brooks, Exercise Physiology Laboratory, Dept. of Integrative Biology, 5101 Valley Life Sciences Bldg., Univ. of California, Berkeley, Berkeley, CA 94720-3140 (E-mail: gbrooks{at}socrates.berkeley.edu).
Received 22 October 1998; accepted in final form 9 March 1999.
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