Glucose production during strenuous exercise in humans: role
of epinephrine
Kirsten
Howlett1,
Mark
Febbraio2, and
Mark
Hargreaves1
1 School of Health Sciences,
Deakin University, Burwood 3125; and
2 Department of Physiology,
The University of Melbourne, Parkville 3052, Australia
 |
ABSTRACT |
The increase in
hepatic glucose production (HGP) that occurs during intense exercise is
accompanied by a simultaneous increase in epinephrine, which suggests
that epinephrine may be important in regulating HGP. To further
investigate this, six trained men were studied twice. The first trial
[control (Con)] consisted of 20 min of cycling at 40 ± 1% peak oxygen uptake
(
O2 peak) followed by
20 min at 80 ± 2%
O2 peak. During the
second trial [epinephrine (Epi)], subjects exercised for 40 min at 41 ± 2%
O2 peak.
Epinephrine was infused during the latter 20 min of exercise and
resulted in plasma levels similar to those measured during intense
exercise in Con. Glucose kinetics were measured using a primed,
continuous infusion of
[3-3H]glucose. HGP was
similar at rest (Con, 11.0 ± 0.5 and Epi, 11.1 ± 0.5 µmol · kg
1 · min
1).
In Con, HGP increased (P < 0.05) during exercise to 41.0 ± 5.2 µmol · kg
1 · min
1
at 40 min. In Epi, HGP was similar to Con during the first 20 min of
exercise. Epinephrine infusion increased
(P < 0.05) HGP to 24.0 ± 2.5 µmol · kg
1 · min
1
at 40 min, although this was less (P < 0.05) than the value in Con. The results suggest that epinephrine
can increase HGP during exercise in trained men; however, epinephrine
during intense exercise cannot fully account for the rise in HGP. Other
glucoregulatory factors must contribute to the increase in HGP during
intense exercise.
liver; catecholamines; glucose kinetics
 |
INTRODUCTION |
HEPATIC GLUCOSE PRODUCTION (HGP) during exercise is
regulated by a complex interaction between both hormonal and neural
mechanisms. Previous research examining the regulation of hepatic
glucose output during exercise has generally focused on mechanisms that operate at moderate intensities (for review, see Ref. 5). Studies in
humans have demonstrated that hepatic glucose output during moderate-intensity exercise is mediated mainly by alterations in
glucagon and insulin (12, 32), although catecholamines, in particular
epinephrine, are important when such alterations do not occur (22). In
contrast, during high-intensity exercise, the changes in glucagon and
insulin are insufficient to account for the marked increase in hepatic
glucose output (6, 30). However, such exercise is associated with an
augmented increase in plasma epinephrine, which has been shown to occur
simultaneously with that in hepatic glucose output (4, 20, 23, 26, 28, 30). These findings suggest, but do not establish, a causal relationship between plasma epinephrine and hepatic glucose output. Only one study has previously infused epinephrine and measured hepatic
glucose output in exercising humans (18). During intense exercise,
infusion of a high physiological dose of epinephrine increased hepatic
glucose output; however, interpretation of the results is complicated
since the subjects had undergone anesthetic blockade of the celiac
ganglion, which impairs sympathetic activity to the liver, pancreas,
and adrenal medulla (18). The aim of the present study was to determine
whether epinephrine was responsible for the increase in hepatic glucose
output during intense exercise in trained men, by infusing epinephrine
during low- to moderate-intensity exercise to obtain plasma levels
similar to those observed during a previous high-intensity exercise bout.
 |
METHODS |
Subjects. Six endurance-trained males
(20.5 ± 0.9 yr, 71.0 ± 2.8 kg, mean ± SE)
volunteered to serve as subjects for the experiment. The experimental
procedures and possible risks of the study were explained to each
subject verbally and in writing. All subjects gave their informed,
written consent, and the experiment was approved by the Human Research
Ethics Committee of The University of Melbourne.
Preexperimental protocol. All subjects
performed an incremental workload test to exhaustion on an
electromagnetically braked cycle ergometer (LODE Instrument, Groningen,
The Netherlands) to determine their peak pulmonary oxygen uptake
(
O2 peak). Mean
O2 peak was 4.34 ± 0.14 l/min. For the day preceding each trial, the subjects
consumed a food package (~14,000 kJ, 80% carbohydrate) and abstained
from strenuous exercise, tobacco, caffeine, and alcohol. In addition,
they were instructed to consume 5 ml tap water/kg body wt upon waking
to ensure euhydration. The subjects reported to the laboratory in the
morning after a 10- to 12-h overnight fast.
Experimental protocol. Each subject
performed two experimental trials, separated by at least 7 days. To
determine whether epinephrine was an important regulator of hepatic
glucose output during intense exercise, epinephrine was infused during
low- to moderate-intensity exercise (Epi) at a rate that was estimated to elevate plasma epinephrine to a level similar to that measured during high-intensity exercise in a control trial (Con). The exercise trials were performed on the same stationary cycle ergometer used in
the
O2 peak
determination. Subjects performed all exercise tests in a laboratory at
a temperature of 20-22°C, and an electric fan circulated air
to minimize thermal stress.
On arrival at the laboratory, all subjects rested quietly on a couch,
and indwelling Teflon catheters were inserted in an antecubital vein of
one arm for blood sampling and in the contralateral arm for infusion.
The catheter for blood sampling was kept patent by flushing with 0.5 ml
of 0.9% saline containing 5 units of heparin every 30 min. After a
priming dose of 40 µCi,
D-[3-3H]glucose
(Du Pont, Biotechnology Systems, Wilmington, DE) was infused
continuously at a rate of 0.40 ± 0.01 µCi/min for the duration of
the 2-h rest period and 40 min of exercise. Upon completion of the rest
period, the subject moved to the cycle ergometer and exercised for
20 min at a workload requiring 40 ± 1%
O2 peak, immediately
followed by a 20-min exercise bout at 80 ± 2%
O2 peak. Venous blood
samples were obtained at 5-min intervals for the last 15 min of the
rest period and throughout exercise for later analysis of plasma
glucose and
[3H]glucose specific
activity. Samples obtained immediately before the commencement of
exercise, at 20, 25, and 30 min, and at the completion of exercise were
analyzed for catecholamines. Additional samples were taken at 0, 20, and 40 min for analysis of plasma lactate, insulin, glucagon, cortisol,
and free fatty acids (FFA). Blood for glucose, lactate, and cortisol
was placed in fluoride heparin tubes, catecholamines and FFA were
placed in plain tubes containing EGTA and reduced glutathione, insulin
was placed in lithium heparin tubes, and glucagon was placed in lithium
heparin tubes containing 200 µl of a protease inhibitor (10%
Trasylol). Upon completion of exercise, the blood samples were spun,
and the plasma was removed and stored at
20°C for later
analysis. Plasma for catecholamine analysis was stored at
80°C. In preparation for the lactate assay, 250 µl of
plasma were deproteinized in 500 µl of 8% perchloric acid and spun
again, and the supernatant was removed and stored at
20°C.
Expired gases were collected in Douglas bags at 10-min intervals during
exercise for measurement of oxygen uptake and respiratory exchange
ratio (RER). Heart rate was measured continuously via telemetry (Polar
sports tester; Polar Electro Finland) and was recorded every 10 min during exercise. Subjects were permitted to drink water ad libitum
during the trials.
For the Epi trial, all subjects undertook the same protocol as
described above. However, the exercise protocol required the subjects
to cycle for 40 min at 41 ± 2%
O2 peak. During the latter 20 min of exercise, an epinephrine solution was delivered via a
three-way stopcock to allow simultaneous infusion of tracer and
epinephrine. Epinephrine was infused in a stepwise manner by a
peristaltic pump. Based on the plasma epinephrine concentrations measured in the Con trial and assuming a clearance of 2.4 l/min (9), an
epinephrine solution (1 µg/ml) was infused at a rate that averaged
0.19 ± 0.04, 0.46 ± 0.09, and 0.76 ± 0.17 µg/min for the exercise intervals of 20-25, 25-30, and
30-40 min, respectively.
In addition, five endurance-trained males (30.8 ± 2.1 yr, 74.4 ± 2.9 kg,
O2 peak = 4.52 ± 0.20 l/min, mean ± SE) were studied during a single
exercise bout. The subjects underwent an identical experimental
protocol as described above except the subjects exercised for 40 min at
40 ± 2%
O2 peak
without epinephrine infusion (WEI).
Analytic techniques. Oxygen and carbon
dioxide contents of dried expirate were analyzed using Applied
Electrochemistry S-3A/II and CD-3A analyzers (Ametek, Pittsburgh, PA),
whereas volume was measured using a Parkinson Cowan gas meter. Plasma
glucose was measured using an automated glucose oxidase method (YSI
2300; Yellow Springs, OH), and lactate was determined using an
enzymatic spectrophotometric method (21). Plasma insulin (Incstar,
Stillwater, MN), glucagon (2), and cortisol (Orion, Espoo, Finland)
were measured by RIA. Plasma catecholamines were determined using a single-isotope, radioenzymatic method (TRK 995; Amersham, Amersham, UK). FFA were measured by an enzymatic colorimetric method (Wako NEFA C
test kit; Wako Chemicals). Plasma
[3H]glucose specific
activity was measured as previously described (14). Rates of plasma
glucose appearance (= HGP) and disappearance (glucose
Rd) at rest and during exercise
were calculated using a modified one-pool non-steady-state model (31)
with the assumption of a pool fraction of 0.65 and estimation of the
apparent glucose space as 25% of body weight. The metabolic clearance
rate (MCR) of glucose was calculated by dividing glucose
Rd by the corresponding plasma
glucose concentration. Data from two trials (Con and Epi) were compared
by a two-way ANOVA for repeated measures. A one-way ANOVA was employed
to compare differences over time for WEI. An unpaired
t-test was utilized to compare the
change in HGP during the final 20 min (20-40 min) of low- to
moderate-intensity exercise either with (Epi) or without (WEI)
epinephrine infusion. The level of significance was set at
P < 0.05. Specific differences were determined using the Student-Newman-Keuls post hoc test. All data are
reported as means ± SE.
 |
RESULTS |
Plasma epinephrine was not different between Con and Epi at rest and
after 20 min of low- to moderate-intensity exercise. In Con, when the
exercise intensity was increased, there was a marked rise
(P < 0.05) in the plasma epinephrine
concentration. Infusion of epinephrine during the last 20 min of
exercise in Epi resulted in plasma levels that were similar to those
measured during high-intensity exercise in Con (Fig.
1).

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Fig. 1.
Plasma epinephrine concentration during 40 min of exercise without
(Con; ) and with (Epi; ) epinephrine infusion commencing at 20 min. Values are means ± SE (n = 6 subjects). No significant difference between trials.
|
|
There were no differences between Con and Epi for oxygen uptake, RER,
and heart rate during the first 20 min of exercise. When the workload
was increased during the final 20 min of exercise in Con, oxygen
uptake, RER, and heart rate increased significantly and were higher
(P < 0.05) than Epi. During the
final 20 min of exercise, in Epi there was no change in oxygen uptake,
but there was a significant increase in RER and heart rate (Table
1).
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Table 1.
Oxygen uptake, RER, and heart rate during 40 min of exercise without
and with epinephrine infusion commencing at 20 min
|
|
Plasma glucose was similar at rest and increased
(P < 0.05) during exercise
in both Con and Epi. During the final 15 min of exercise, plasma
glucose was significantly higher in Con compared with Epi (Fig.
2). HGP was similar at rest between trials
(Con, 11.0 ± 0.5 and Epi, 11.1 ± 0.5 µmol · kg
1 · min
1).
In Con, HGP increased (P < 0.05) to
17.7 ± 1.0 µmol · kg
1 · min
1
after 20 min of low- to moderate-intensity exercise. When the exercise
intensity was increased, there was a marked rise
(P < 0.05) in HGP to a peak of 41.0 ± 5.2 µmol · kg
1 · min
1
at 40 min. In Epi, HGP was not different from Con during the first 20 min of exercise (16.6 ± 1.2 µmol · kg
1 · min
1
at 20 min). During the final 20 min of exercise, infusion of epinephrine resulted in an increase (P < 0.05) in HGP to 24.0 ± 2.5 µmol · kg
1 · min
1
at 40 min of exercise, although this was less
(P < 0.05) than Con (Fig. 2).
Glucose Rd and MCR were not
different between Con and Epi at rest. In Con, glucose
Rd and MCR increased
(P < 0.05) and were greater
(P < 0.05) than Epi during the
latter stages of exercise. Glucose
Rd and MCR were not affected by
epinephrine infusion during exercise (Fig.
3).

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Fig. 2.
Plasma glucose concentration and hepatic glucose production (HGP)
during 40 min of exercise without (Con) and with (Epi)
epinephrine infusion commencing at 20 min. Values are means ± SE
(n = 6).
P < 0.05, significant difference
from Epi (*) and from 20 min ( ).
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Fig. 3.
Whole body glucose uptake (glucose
Rd) and metabolic clearance rate
(MCR) during 40 min of exercise without (Con) and with (Epi)
epinephrine infusion commencing at 20 min. Values are means ± SE
(n = 6).
P < 0.05, significant difference
from Epi (*) and 20 min ( ).
|
|
Plasma insulin, glucagon, and the glucagon-to-insulin molar ratio were
not different between Con and Epi at rest and during exercise (Table
2). During the first 20 min of exercise,
plasma norepinephrine, cortisol, and lactate were not different between trials. In Con, plasma norepinephrine, cortisol, and lactate increased (P < 0.05) during the final 20 min
of exercise and were greater (P < 0.05) than Epi. Infusion of epinephrine did not alter the plasma
concentrations of norepinephrine, cortisol, and lactate (Table 2).
Plasma FFA were significantly different between Con and Epi at rest and
during exercise. In Con, plasma FFA decreased (P < 0.05) during the high-intensity
exercise bout, whereas infusion of epinephrine in Epi resulted in an
increase (P < 0.05) in plasma FFA
levels (Table 2).
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Table 2.
Plasma insulin, glucagon, glucagon-insulin molar ratio, norepinephrine,
cortisol, free fatty acids, and lactate during 40 min of exercise
without and with epinephrine infusion commencing at 20 min
|
|
In WEI, there was no change in oxygen uptake (1.83 ± 0.11 l/min, average value), RER (0.87 ± 0.02), and heart rate (107 ± 5 beats/min) during 40 min of low- to moderate-intensity exercise. There was no significant change in plasma glucose during exercise (Table 3), and the increases in HGP, MCR,
and glucose Rd were not
statistically significant (Table 3). Plasma epinephrine did not rise
during exercise, unlike plasma norepinephrine, which was elevated
(P < 0.05) after 40 min of exercise
(Table 3). Plasma levels of glucagon, insulin, FFA, and lactate did not
change during exercise (Table 3). The change in HGP during the final 20 min of low- to moderate-intensity exercise in Epi (7.4 ± 2.1 µmol · kg
1 · min
1)
was greater (P < 0.05) than that in
WEI (2.3 ± 0.9 µmol · kg
1 · min
1).
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Table 3.
HGP, glucose Rd, MCR, plasma hormones and metabolites
during 40 min of exercise at 40 ± 2%
O2 peak without
epinephrine infusion
|
|
 |
DISCUSSION |
The results from the present study suggest that in trained men the
marked increase in plasma epinephrine observed during exercise at 80%
O2 peak cannot fully
account for the rise in hepatic glucose output. Other glucoregulatory
factors must contribute to the increase in glucose production during
intense exercise.
Previous studies have proposed that catecholamines, specifically
epinephrine, are the main mediators of the increment in hepatic glucose
output during intense (>80%
O2 peak) exercise (20, 23, 26, 30). In contrast, the results from the present study argue
against epinephrine as the major humoral mediator of the increase in
hepatic glucose output. Infusion of epinephrine during low- to
moderate-intensity exercise that elevated plasma epinephrine to a level
similar to that measured during intense exercise in Con (Fig. 1) could
only account for ~30% of the rise in hepatic glucose output (Fig.
2). It is possible that, during intense exercise, changes in the
internal milieu may influence the effect of the exercise-induced rise
in epinephrine on HGP such that, in the present study, the increase in
the epinephrine concentration, per se, during low- to
moderate-intensity exercise may have underestimated the contribution of
epinephrine to glucose production during intense exercise. However, a
recent study in dogs showed that infused phentolamine and propranolol
in the portal vein to selectively block hepatic
- and
-adrenoceptors, respectively, were unable to attenuate the rise in
hepatic glucose output during heavy (85% of maximum heart rate)
exercise (7). Taken together, these findings suggest that epinephrine
may not play the major role in mediating the increase in hepatic
glucose output during intense exercise.
Given that the augmented increase in plasma epinephrine observed during
intense exercise cannot fully account for the rise in hepatic glucose
output (Fig. 2), other glucoregulatory factors must contribute to the
increase in glucose production. Sympathetic neural innervation of the
liver has been proposed to play an important role in the regulation of
hepatic glucose output during exercise in humans (6, 13, 23, 26, 30).
In contrast, HGP was not reduced during intense exercise in normal
subjects when sympathetic activity to the liver was impaired by
anesthetic blockade of the celiac ganglion (18) and in liver transplant
patients (19). These findings suggest that sympathetic neural activity
does not play a role in hepatic glucoregulation during exercise in
these circumstances. However, as indicated by Sigal et al. (30), it is
difficult to extrapolate the findings from liver transplant patients to
normal healthy individuals. Furthermore, hepatic neural activation may
be more important during exercise at higher absolute or relative
intensities (6) than at those used in these studies. Given the evidence
outlined above, the role of sympathetic liver nerves in the regulation
of glucose production during exercise in humans remains equivocal. In
the present study, plasma norepinephrine correlated significantly with
the increase in HGP in Con (r = 0.70, P < 0.05). Thus it is possible that
activation of sympathetic liver nerves may account, at least in part,
for the rise in hepatic glucose output during intense exercise.
In agreement with previous studies (6, 23, 26, 30), the findings from
this study suggest that pancreatic hormones are unlikely to account for
the rise in hepatic glucose output during intense exercise, as plasma
insulin, glucagon, and the molar ratio were not different between
trials (Table 2). However, it is possible that peripheral levels of
insulin and glucagon may not reflect significant changes in the portal
vein concentration of these hormones. A small increment in the portal
vein concentration of glucagon and/or a decrement in insulin could
account for the marked increase in hepatic glucose output in Con (Fig.
2).
Factors other than catecholamines and pancreatic hormones could be
responsible for the increase in hepatic glucose output during intense
exercise (Fig. 2). Elevated plasma cortisol levels in Con (Table 2) may
contribute to the rise in hepatic glucose output. The effect of this
hormone on glucose production during exercise has not been directly
established. However, cortisol is likely to play only a minor role (for
review, see Ref. 8), as this hormone acts by increasing
gluconeogenesis, which does not contribute significantly to hepatic
glucose output at high intensities. Changes in the plasma glucose
concentration may also contribute to the increase in glucose output,
although in the present study this is unlikely as elevated plasma
glucose levels (Fig. 2) have been shown to attenuate the rise in
hepatic glucose output during strenuous exercise (11, 14, 24). Hepatic
blood flow was not measured, but it is possible that reduced splanchnic blood flow during high-intensity exercise could alter glucose production (17). Decreased blood flow, which is thought to reflect an
increase in local vascular resistance mediated by increased sympathetic
nervous activity (for review, see Ref. 29), could affect hepatic
glucose output either directly or indirectly by altering the delivery
of hormones and substrates to the liver. However, this remains to be
determined. Furthermore, it cannot be excluded that the possibility of
other, as yet unidentified, factors may contribute to the increase in
hepatic glucose output observed during high-intensity exercise.
The results from the present study also suggest that, in trained men
during low- to moderate-intensity exercise, infusion of epinephrine
that results in plasma concentrations that were higher than those
normally seen at this exercise intensity can increase hepatic glucose
output (Fig. 2). It is unlikely that the rise in hepatic glucose output
in Epi was simply a time-dependent increase, since in an additional
group of five trained males who exercised for 40 min at 40 ± 2%
O2 peak
without epinephrine infusion, hepatic glucose output did not increase
significantly from 20 to 40 min of exercise (Table 3). The change in
HGP during the final 20 min of low- to moderate-intensity exercise with
epinephrine infusion was significantly greater than that in those
subjects who did not receive the epinephrine infusion (WEI). The effect of elevated plasma epinephrine levels on HGP during exercise is in
accordance with previous findings (18) and is likely a result of
epinephrine directly stimulating liver glycogenolysis. Epinephrine could also increase the supply of gluconeogenic precursors by stimulating muscle glycogen breakdown (1, 25, 27).
It has been suggested that an increase in the plasma epinephrine
concentration could reduce muscle glucose uptake during exercise (15)
as a result of direct effects on muscle glucose transport (3) and/or
indirect effects on glucose metabolism via changes in muscle
glycogenolysis (16) and FFA availability (10). In contrast, results
from the present study suggest that epinephrine infusion does not
significantly influence muscle glucose uptake and glucose clearance
during exercise (Fig. 3). Similarly, muscle glucose uptake was not
altered during exercise in celiac ganglion-blocked humans either with
or without infusion of epinephrine (18). However, in the present study,
epinephrine infusion resulted in an increase in carbohydrate oxidation
(Table 1), which, in the absence of changes in glucose
Rd, suggests that epinephrine may have stimulated muscle glycogen degradation.
In summary, the results from the present study suggest that, in trained
men, the augmented increase in plasma epinephrine observed during
intense exercise cannot fully account for the magnitude of the rise in
hepatic glucose output. Other glucoregulatory factors must also
contribute to the increase in glucose production during intense exercise.
 |
ACKNOWLEDGEMENTS |
We acknowledge the assistance of Joseph Proietto in the conduct of
this study, the advice of Murray Esler in relation to epinephrine infusion, and Damien Angus, Michael Christopher, Jane Dancey, Donna
Lambert, and Rebecca Starkie for excellent technical assistance.
 |
FOOTNOTES |
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 correspondence: M. Hargreaves, School of Health Sciences,
Deakin University, Burwood 3125, Australia (E-mail:
mharg{at}deakin.edu.au).
Received 16 November 1998; accepted in final form 3 March 1999.
 |
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