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-estradiol decreases glucose Ra but
not whole body metabolism during endurance exercise
Departments of Medicine (1 Rehabilitation and 3 Neurology) and 2 Kinesiology, McMaster University, Hamilton, Ontario, Canada L8N 3Z5
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The female sex
hormone 17
-estradiol (E2) has been shown to increase
lipid and decrease carbohydrate utilization in animals. We
administrated oral E2 and placebo (randomized, double
blind, crossover) to eight human male subjects for 8 days (~3 mg/day) and measured respiratory variables, plasma substrates, hormones (E2, testosterone, leptin, cortisol, insulin, and
catecholamines), and substrate utilization during 90 min of endurance
exercise. [6,6-2H]glucose and
[1,1,2,3,3-2H]glycerol tracers were used to calculate
substrate flux. E2 administration increased serum
E2 (0.22 to 2.44 nmol/l, P < 0.05) and
decreased serum testosterone (19.4 to 11.5 nmol/l, P < 0.05) concentrations, yet there were no treatment effects on any of the
other hormones. Glucose rates of appearance (Ra) and
disappearance (Rd) were lower, and glycerol
Ra-to-Rd ratio was not affected by
E2 administration. O2 uptake, CO2
production, and respiratory exchange ratio were not affected by
E2; however, there was a decrease in heart rate (P < 0.05). Plasma lactate and glycerol were
unaffected by E2; however, glucose was significantly higher
(P < 0.05) during exercise after E2
administration. We concluded that short-term oral E2 administration decreased glucose Ra and Rd,
maintained plasma glucose homeostasis, but had no effect on substrate
oxidation during exercise in men.
gender differences; glycogenolysis
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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MOST (10, 12, 16, 26, 33, 35, 36), but not all (4, 5, 10), human studies have found that female subjects have a lower respiratory exchange ratio (RER) during endurance exercise compared with male subjects. It is critical to control for the time of menstrual cycle, duration of training, matching of the genders for oxygen consumption relative to lean body mass, and the measurement and provision of isoenergetic diets in gender comparison studies. A number of recent studies (10, 16, 24, 33, 34, 36) have controlled for these variables, and the overall conclusion was that women oxidize proportionately more lipid and less carbohydrate during submaximal endurance exercise compared with men. It is unclear whether these gender differences were due to differences in sex hormones per se or were related to the known gender differences in body fat content and energy intake (25), even when the latter two are expressed relative to lean body mass (33, 34, 36).
Results from animal studies suggest that 17-estradiol
(E2) plays a major role in the determination of substrate
selection during endurance exercise (8, 17, 18, 29). For
example, the provision of E2 to male or oophorectomized
female rats has resulted in a sparing of both skeletal and hepatic net
glycogen utilization (17, 18) and an increase in the
proportion of lipid oxidized during treadmill exercise
(15). In addition, studies have found an increase in the
activity of skeletal muscle lipoprotein lipase activity (8, 14,
27, 38), intramuscular triglyceride concentration
(8), and plasma free fatty acid concentration
(8). Taken together, these data indicate that E2 can result in hepatic, cardiac, and skeletal muscle
glycogen sparing, which may be secondary to an increased utilization of lipid during endurance exercise.
The provision of E2 to amenorrheic women has been shown to reduce glucose rate of appearance (Ra), yet it had no effect on glycerol Ra during submaximal endurance exercise (31). The authors also reported a reduction in plasma epinephrine concentration during exercise after E2 administration (31). Our laboratory has recently found that transdermal E2 administration did not result in an attenuation of skeletal muscle glycogen utilization in men (35). Furthermore, our group has found that skeletal muscle glycogen utilization is similar for male and female athletes performing cycle ergometry (33, 34). Together, these data suggest that E2 may have a more significant effect on hepatic glucose production (gluconeogenesis and glycogenolysis) compared with skeletal muscle glycogenolysis.
In previous studies investigating E2 administration effects during endurance exercise metabolism, our laboratory (35) and Ruby and colleagues (31) have used a transdermal patch. This resulted in an approximate doubling of plasma E2 concentration (normal follicular concentration) (31, 35), yet these increases were far less than those seen in an animal model (17, 18). Recently, an oral E2 tablet has become available (Estrace, Robertson Pharmaceutical) that has allowed for a delivery rate similar to those used in animal studies (normal luteal concentration).
Therefore, it was the purpose of this study to examine the effect of oral E2 administration on glycerol and glucose turnover and whole body metabolism during endurance exercise in human male subjects. Furthermore, we wanted to measure the serum concentration of various hormones that can play a role in substrate selection during exercise. We hypothesized that higher dose E2 administration (normal luteal concentrations) would result in a lower RER, lower catecholamines, a lower glucose Ra, and a higher glycerol Ra during endurance exercise in men.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects.
Eight healthy active male volunteers participated in the study [age,
25 ± 4 yr; weight, 76.2 ± 7.0 kg; height, 179 ± 8 cm; peak oxygen uptake (
O2 peak), 4.0 ± 0.4 l/min and 53.3 ± 6.7 ml · kg
1 · min1]. Informed
consent was obtained after the subjects were given a description of the
study and advisement of the risks and benefits of participation in
accordance with, and under approval of, the Research Ethics Committee.
Protocol.
A progressive exercise test on an electronically braked cycle ergometer
was used to determine O2 peak as
previously described (26, 33, 34). The progressive cycle
test took place within 2 wk of the initiation of the study. The
O2 peak was used to estimate the work
intensity required to elicit 60% of the subject's
O2 peak for subsequent testing.
1 · min1 for
glucose and glycerol tracers, respectively, at rest for 90 min. At the
onset of exercise, the infusion rate was increased in a stepwise
fashion at 0, 5, and 10 min of exercise to ~0.33 and ~0.075,
~0.44 and ~0.10, and ~0.55 and ~0.125
µmol · kg1 · min1, for
glucose and glycerol tracers, respectively. The infusion rate remained
at ~0.55 (glucose) and ~0.125
µmol · kg1 · min1
(glycerol) for the remainder of the 90 min of exercise. Blood samples
were drawn 75 min after the initiation of the constant infusion (
15
min); at rest (0 min); and at 30, 60, 75, and 90 min during exercise.
Blood samples collected for the analysis of metabolites and substrates
(glucose, glycerol, lactate, free fatty acids) and cortisol were
collected into heparinized tubes and centrifuged immediately, and the
plasma was stored at 50°C for subsequent analysis. For
catecholamine determination, 5 ml of whole blood were added to a tube
containing 100 µl of EDTA and reduced glutathione. The tube was
centrifuged at 2,000 g for 10 min, and the plasma was stored
at 80°C for subsequent analysis. Blood samples collected for
hormone (leptin, insulin, testosterone, and E2) analysis
were allowed to stand for 10 min in untreated tubes and were then
centrifuged, and the serum was stored at 50°C for subsequent
analysis. The total amount of blood that was removed for each trial was
consistent between trials and amounted to ~85 ml/trial.
Respiratory measurements were made by using a computerized open-circuit
gas collection system as described previously (33, 34).
Respiratory gases were collected at 30, 60, 75, and 90 min of exercise.
Heart rate was also monitored continuously throughout the 90 min of
exercise, and a mean 2.0 min were recorded at the same time points as
for respiratory gases.
Analysis. Plasma lactate concentration was analyzed with a lactate analyzer (model 23L, Yellow Springs Instruments, Yellow Springs, OH). Plasma glucose was analyzed by using a glucose oxidase colorimetric assay [glucose (Trinder) 315, Sigma Diagnostics, St. Louis, MO]. Plasma glycerol concentration was determined by using an enzymatic colorimetric assay [triglyceride (GPO-Trinder), Sigma Diagnostics].
Catecholamines (epinephrine and norepinephrine) were analyzed by using HPLC (injector WISP 710B and pump model 570, Waters, Milford, MA) techniques and electrochemical detection. For catecholamine extraction, 1 ml of plasma was added to a 1.5-ml microcentrifuge tube containing 20 mg of acid-washed alumina, 400 µl of Tris buffer (243.6 g Tris/l and 2 g EDTA/l, pH 8.8), and 10 µl of the internal standard 3,4-dihydroxybenzylamine (1 ng/10 µl). The samples were vortexed, shaken for 10 min, and then centrifuged. The supernatant was removed, and the alumina was washed three times with 9× distilled water. The catecholamines were then extracted from the alumina with 100 µl of 0.25 N acetic acid. The eluent (45 µl) was injected onto a HPLC column (reverse-phase symmetry shield, RP8, 3.9 × 150 mm, Waters). The mobile phase consisted of 3% methanol, sodium monobasic phosphate (6.9 g/l), heptane sulfonic acid (250 mg/l), and EDTA (80 mg/l), adjusted to a pH of 3.6. The flow rate was 1.25 ml/min at ~2,400 psi. The catecholamines were detected electrochemically (Coulochem II, ESA, Chelmsford, MA), and chromatography was analyzed by computer (Millenium, Waters). E2, testosterone, and insulin were analyzed by using a single incubation radioimmunoassay (Coat-a-count: kits TKE21, TKTE1, and TKIN5, Diagnostics Products, Los Angeles, CA). Serum leptin concentration was analyzed by radioimmunoassay using a rabbit anti-human polyclonal antibody (Linco Research, St. Charles, MO). Plasma cortisol concentration was analyzed by using a single incubation radioimmunoassay (Coat-a-Count: kit TKC01, Diagnostics Products). Isotopic enrichment of glucose and glycerol was determined by using gas chromatography-mass spectrometry (GC-MS; GC model 6890 and MS model 5973, Hewlett-Packard, Fullerton, CA) of the pentaacetate and tris-trimethylsilyl derivatives, respectively. In preparation for the GC-MS analysis, each sample was deproteinized with barium hydroxide and zinc sulfate. The supernatant was then transferred to an anion-cation (AG 1X8-400 and AG 50X8-400, Sigma Chemical) exchange column, and the eluted extract was lyophilized. The pentaacetate derivative of glucose was prepared by adding 100 µl of 2:1 solution of acetic anhydride and pyridine to each sample. The samples were then heated for 20 min at 65°C. The Tris-trimethylsilyl derivative of glycerol was prepared by adding 100 µl of 2:1 solution of N,O-bis(trimethylsilyl)trifluoroacetamide (Supelco, Bellefonte, PA) and pyridine to each sample. The samples were heated for 30 min at 80°C. For each derivative, 1 µl was injected into the gas chromatography oven. The capillary column used for both isotopes was a 15-m fused silica capillary column, with 0.2-mm diameter and 0.2-µm film thickness (Supelco). For GC-MS analysis of glucose, the initial oven temperature was set at 150°C and was increased 30°C/min until a final temperature of 250°C was reached. The carrier gas was helium, and the split-pulse injection flow rate was set 9 ml/min. The source temperature was set at 230°C, and the quadrapole temperature was set at 106°C. Mass analysis was performed in the electron impact ionization (i.e., Ei+) mode to monitor selected ions with a mass-to-charge ratio of 200:202 atomic mass units. For the analysis of glycerol, the initial oven temperature was set at 126°C and was increased 30°C/min until a final temperature of 220°C was reached. The carrier gas was helium, and the split-pulse injection flow rate was set at 25 ml/min. The source temperature was set at 230°C, and the quadrapole temperature was set at 106°C. Electronic impact ionization mode was used for fragmentation, and selective ion monitoring was used to monitor glycerol fragments with a mass-to-charge ratio of 205:208 atomic mass units. Ra and rate of disappearance (Rd) of glucose and glycerol were calculated according to the Steele equation (32). The Steele equation was modified for use with stable isotopes according to Romijn et al. (28), because the amount of tracer infused is no longer considered negligible. The concentration (C) of the tracee at time t can be calculated from the (measured) concentration (Cm) and the enrichment (E) at that time
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Statistical analysis.
The physical characteristics of the participants and the hormone
concentrations were analyzed by using a one-way ANOVA. All other data
were analyzed by using a two-way repeated-measures ANOVA, with
condition (placebo, E2) being the first within variable and
time (t = 0, 30, 60, 75, 90 min) being the second
variable. When significance was obtained, the location of the
difference was determined by using Tukey's post hoc test. The level of
significance was set at P < 0.05. Values presented in
Tables 1-4 and the text are means ± SD, and values presented
in Figs. 1 and 2 are means ± SE for clarity purposes.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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E2 administration for 8 days resulted in an increase in plasma E2 concentration (P < 0.001) and a decrease in testosterone concentration (P < 0.05, Table 1). Eight days of E2 administration did not alter plasma insulin or serum leptin concentration at rest (Table 1).
The 90-min exercise bout was performed at the same absolute and
relative workload for the E2 and placebo trials (58.4 and 58.3% O2 peak, respectively). There
was no difference in oxygen consumption, carbon dioxide production, or
RER for the E2 vs. placebo trial administration (Table
2). Although the intensity was not
different between the two trials, heart rate was significantly lower
after E2 compared with the placebo administration (Table 2).
The administration of E2 did not change resting lactate concentration or the lactate response during exercise. Plasma lactate concentration did increase with time for both the E2 and placebo conditions (Table 3). Plasma glycerol concentrations were also not affected by E2 administration at rest or during the 90 min of exercise; however, plasma glycerol concentration did increase (P < 0.001) with exercise in both conditions (Table 3). Plasma glucose concentration was significantly higher (P < 0.01) after E2 compared with placebo administration (Table 3). Plasma glucose was lower at t = 75 and 90 min of exercise compared with t = 0 and 30 min (P < 0.01).
The administration of E2 did not change resting cortisol concentration or the cortisol response during prolonged exercise. Plasma cortisol concentrations decreased with the onset of exercise; however, this decrease was not significant and was followed by an increase during exercise (concentration at t = 30 min was significantly lower than at t = 90 min of exercise; P < 0.05; Table 4).
The E2 administration did not change resting catecholamine (norepinephrine or epinephrine) concentrations or the catecholamine response during prolonged exercise. Norepinephrine and epinephrine concentrations increased during prolonged exercise (P < 0.001 and P < 0.01; Table 4).
Glucose Ra and Rd were significantly lower (P < 0.05) during the E2 compared with the placebo trial (Fig. 1). Glucose Ra was higher at t = 30, 60, 75, and 90 min compared with rest and was higher at t = 90 min compared with t = 30, 60, and 75 min of exercise (P < 0.001; Fig. 1). The metabolic clearance rate (MCR) of glucose was significantly lower during E2 administration compared with placebo, and MCR increased during exercise (P < 0.05). MCR at t = 0 min was lower than all other time points. At t = 30 and 60 min, MCR was lower than at t = 75 and 90 min of exercise (P < 0.001; Fig. 1).
Glycerol Ra and Rd were not affected by E2 administration at rest or during exercise. Glycerol Ra was significantly higher at t = 30, 60, 75, and 90 min of exercise compared with t = 0 min (P < 0.001; Fig. 2).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study has demonstrated that E2 administration resulted in a reduction in glucose Ra and MCR, a higher plasma glucose concentration, and a reduction in heart rate during endurance exercise in men. These E2-mediated effects were independent of plasma cortisol or catecholamine concentrations. There were no effects of E2 administration on glycerol Ra or whole body substrate oxidation during endurance exercise in men.
Several studies in humans have demonstrated a lower RER during endurance exercise for women compared with men (10, 12, 16, 26, 33, 34, 36). These findings implied that women oxidize proportionately more lipid and less carbohydrate during submaximal endurance exercise compared with men. In these studies, there were careful controls for the key parameters of antecedent diet, menstrual cycle phase, and matching based on training history and current training status (10, 16, 27, 33, 34, 36). The mechanism(s) behind these gender differences in metabolism are not clear, although animal data have suggested that the female sex hormone E2 may play an important role in substrate selection during exercise (3, 8, 13, 15, 17, 18, 29). For example, estradiol administration in the rat model has been shown to increase lipid and decrease carbohydrate oxidation (8, 15, 17), decrease skeletal muscle and hepatic and cardiac glycogenolysis (17, 18, 29), and increase skeletal muscle triacylglycerol (TG) content and lipoprotein lipase activity (8, 27, 38). Together, these data suggest that E2 is likely responsible for a significant proportion of the observed gender differences in exercise metabolism seen in humans (10, 12, 16, 26, 33, 34, 36). To date, there has not been an investigation into the potential for E2 to alter whole body carbohydrate and glycerol flux when given at doses that would yield plasma concentrations close to those observed in the animal models. Although, in the present study, we did not suppress testosterone concentrations to female levels, we do not feel that this would influence our outcomes. For example, our results are similar to those of Ruby and colleagues (31), who examined the metabolic effects of E2 on exercise metabolism in amenorrheic women in whom testosterone would clearly be very low. Finally, in the animal studies (8, 17, 18, 27, 29, 38), the results are similar whether male (higher testosterone) or oophorectomized female (lower testosterone) rats are given E2.
The finding of a reduction in glucose Ra in the present study is similar to that of a recent study reported by Ruby and colleagues (31) using transdermal E2 administration in amenorrheic women. This latter study also found no effect of estradiol treatment on glycerol Ra or whole body substrate oxidation (31). In the study by Ruby and colleagues, the increase in plasma E2 was ~60% (approximately follicular concentration) (23), yet it was >1,000% in the present study (approximately luteal concentration). The similarity of the results between these two studies implies that the failure to find an effect of E2 on glycerol Ra was not likely a dose-related phenomenon. Taken together, these data are consistent in demonstrating that short-term E2 administration has a small but significant effect on glucose flux, with no effect on whole body lipolysis or whole body substrate oxidation.
Data obtained from animals provided support for the observed reduction in glucose Ra in response to E2 administration (17, 18, 29). The administration of E2 to male rats resulted in significant hepatic glycogen sparing in response to 2 h of treadmill running (18). These latter findings were also confirmed by this same group, which showed a 91% reduction in hepatic glycogen utilization for sham-injected, compared with a 54% reduction in hepatic glycogen concentration for E2-treated animals after 2 h of treadmill running (17). However, these studies do not provide direct evidence for the mechanism of action of E2 (i.e., increased gluconeogenesis vs. decreased glycogenolysis).
It has been shown that estradiol treatment decreased the maximal activity of hepatic phosphoenol- pyruvate carboxykinase in oophorectomized rats (20). Estradiol treatment of female rats resulted in a reduction in [U-14C]alanine incorporation into glucose, suggesting a reduction in hepatic gluconeogenesis from amino acid precursors (21). Together, these data provide strong evidence that estradiol directly reduces hepatic gluconeogenesis. Although there is a strong positive correlation between plasma cortisol concentration and gluconeogenesis (37), we did not find that plasma cortisol concentration was affected by E2 treatment. In addition, Ruby and colleagues (31) found that E2 treatment lowered plasma epinephrine concentration during exercise, which could partially explain the reduction in glucose Ra (19). However, our data show that a reduction in glucose Ra can occur independently of catecholamine concentration. The results of the present study implied that E2 had a direct effect on glucose kinetics that did not appear to alter whole body metabolism. Also of interest was the observation that both transdermal E2 (31, 35) and oral E2 showed similar effects on glucose Ra in humans. These findings suggest that first-pass hepatic clearance of splanchnic-derived E2 is not required for the observed hepatic effects.
Despite the reduction in glucose Ra, there was a higher plasma glucose concentration throughout exercise in the present study for the E2 treatment. This corresponded to a lower MCR of glucose. The estradiol-mediated reduction in glucose Ra-to-Rd ratio with no change in whole body RER indirectly suggested an increase in skeletal muscle glycogen utilization and/or an increase in lipid utilization. An increase in skeletal muscle glycogen utilization is opposite to the conclusions based on direct muscle glycogen measurements in humans (33, 36) and rats (17, 18, 29).
An increase in lipid oxidation by the skeletal muscle could still explain the apparent paradox described above; however, the whole body RER measurements did not support this hypothesis. It is possible that whole body RER does not reflect tissue-specific respiratory quotient (RQ). For example, Brooks and colleagues (1) have reported that working muscle RQ and whole body RER can be disparate during endurance exercise (i.e., a reduction in whole body RER has been found after training with no change in muscle RQ). In the present study, we did not find an effect of E2 on whole body lipolysis (glycerol Ra) or whole body lipid oxidation. These findings do not rule out an effect of E2 on lipid metabolism partially for the reasons stated above. Furthermore, there may be tissue-specific effects of E2. For example, estradiol administration resulted in a dose-dependent increase in the maximal activity of hepatic acetyl-CoA carboxylase and fatty acid synthetase in rats (20). Furthermore, E2 results in an increase in resting muscle TG content and induces a net synthesis of TG in red vastus muscle during 2 h of treadmill exercise (8). Thus, if TG synthesis is occurring during exercise, the whole body RER may be falsely elevated (TG synthesis RER exceeds unity) and not reflect tissue-specific metabolism. This highlights the need to measure tissue-specific models of metabolism in response to an intervention. One final confounding variable is that there is an ongoing debate as to the validity of glycerol Ra as a mediator of whole body lipolysis (7). Therefore, future studies examining the metabolic effects of E2 and gender differences should include whole body and stable isotopic measurements in combination with artriovenous balance and direct muscle measurements.
Perhaps the best evidence for and effect of E2 to maintain
plasma glucose concentration comes from observations made in transgenic mice that have a double knockout of the peroxisome
proliferator-activated receptor-
(PPAR- -/-) (6). If
these PPAR- -/- mice are given etomoxir (an inhibitor of carnitine
palmitoyltransferase I), the males develop fatal hypoglycemia, whereas
only 25% of the females show the same phenotype (6). The
hypoglycemic effect of the PPAR- -/- genotype plus etomoxir was
prevented entirely when the male mice were pretreated with
E2 (6).
Finally, the finding of a reduction in heart rate during endurance exercise was unexpected and not seen in our laboratory's pilot work with transdermal E2 (35) nor in the study by Ruby and colleagues (31). However, there was a reduction in epinephrine concentration both at 90 min of endurance exercise and after a maximal exercise bout with E2 treatment (31). We measured catecholamine concentrations in the present study, yet, in contrast to the results of Ruby and colleagues, we did not observe a decrease in plasma epinephrine concentration during endurance exercise after the administration of E2 in men. Therefore, from the findings of the present study, we cannot explain the decrease in heart rate after the administration of E2 in men during endurance exercise. Lower muscle sympathetic nerve activity has also been shown in female compared with male human subjects during exercise (9). It is possible that sympathetic and plasma catecholamine may not be 100% concordant. In addition, heart rate could be attenuated by factors such as fluid volume shifts. For example, an expansion of plasma volume could attenuate the exercise-induced rise in heart rate (22, 30). To our knowledge, the effect of E2 on fluid volume has not been investigated.
In summary, we have demonstrated that E2 administration can alter glucose turnover yet have no apparent effect on whole body metabolism or plasma and serum concentrations of a variety of hormones during exercise. Future studies are needed to understand the mechanism(s) behind gender differences in metabolism during endurance exercise.
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ACKNOWLEDGEMENTS |
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This study was funded by the Natural Science and Engineering Research Council of Canada.
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. A. Tarnopolsky, Dept. of Neurology, Rm. 4U4, McMaster Univ. Medical Centre, 1200 Main St. West, Hamilton, Ontario, Canada L8N 3Z5 (E-mail: tarnopol{at}FHS.McMaster.ca).
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 23 May 2000; accepted in final form 31 July 2000.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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