Vol. 278, Issue 3, E444-E451, March 2000
Hepatic 
- and 
-adrenergic receptors are not essential
for the increase in Ra during exercise in diabetes
Robert H.
Coker1,
D. Brooks
Lacy2,
Phillip
E.
Williams3, and
David H.
Wasserman1
1 Department of Molecular Physiology and
Biophysics, 2 Diabetes Research and Training
Center, and 3 Department of Surgery, Vanderbilt
University School of Medicine, Nashville, Tennessee 37232-0615
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ABSTRACT |
The purpose of this study was to determine the role of
direct hepatic adrenergic stimulation in the control of endogenous glucose production (Ra) during moderate exercise in poorly
controlled alloxan-diabetic dogs. Chronically catheterized and
instrumented (flow probes on hepatic artery and portal vein) dogs were
made diabetic by administration of alloxan. Each study consisted of a
120-min equilibration, 30-min basal, 150-min moderate exercise, 30-min
recovery, and 30-min blockade test period. Either vehicle (control;
n = 6) or 
(phentolamine)- and 
(propranolol)-adrenergic blockers (HAB; n = 6) were infused in the portal vein. In both groups, epinephrine (Epi) and norepinephrine (NE) were infused in the
portal vein during the blockade test period to create
suprapharmacological levels at the liver. Isotopic
([3-3H]glucose,
[U-14C]alanine) and arteriovenous difference
methods were used to assess hepatic function. Arterial plasma glucose
was similar in controls (345 ± 24 mg/dl) and HAB (336 ± 23 mg/dl)
and was unchanged by exercise. Basal arterial insulin was 5 ± 1 mU/ml
in controls and 4 ± 1 mU/ml in HAB and fell by ~50% during
exercise in both groups. Basal arterial glucagon was similar in
controls (56 ± 10 pg/ml) and HAB (55 ± 7 pg/ml) and rose similarly,
by ~1.4-fold, with exercise in both groups. Despite greater arterial
Epi and NE levels in HAB compared with controls during the basal and
exercise periods, exercise-induced increases in catecholamines from
basal were similar in both groups. Gluconeogenic conversion from
alanine and lactate and the intrahepatic efficiency of this process
were increased by twofold during exercise in both groups.
Ra rose similarly by 2.9 ± 0.7 and 2.7 ± 1.0 mg · kg
1 · min1
at time = 150 min during exercise in controls and HAB. During the
blockade test period, arterial plasma glucose and Ra rose to 454 ± 43 mg/dl and 11.3 mg · kg1 · min1
in controls, respectively, but were essentially unchanged in HAB. The
attenuated response to the blockade test in HAB substantiates the
effectiveness of the hepatic adrenergic blockade. In conclusion, these
results demonstrate that direct hepatic adrenergic stimulation does not
play a role in the stimulation of Ra during exercise in
poorly controlled diabetes.
catecholamines; glucagon; insulin; liver; glucose production
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INTRODUCTION |
EXERCISE-INDUCED CHANGES in glucagon and insulin
stimulate endogenous glucose production (Ra) during
moderate exercise in the healthy state. This exercise-induced increment
in Ra is matched by an increase in glucose utilization
(Rd), which results in the maintenance of glucose
homeostasis (26). In contrast, the exercise-induced increment in
Ra in the poorly controlled diabetic state occurs despite
hyperglycemia which, by itself, is great enough to support the
requirement for glucose for ~45 min (25, 27). The needless increase
in Ra is often accompanied by an elevation in sympathetic drive that may contribute to the deleterious effects of exercise in the
poorly controlled diabetic state (7). Studies with -adrenergic blockade in the depancreatized dog model have shown a small reduction in Ra during moderate exercise (2). However, in addition to the reduction of Ra in these previous studies, arterial
free fatty acids (FFA) and gluconeogenic precursors were also reduced
due to the -adrenergic blockade, which in turn, would decrease their hepatic delivery. The limitation of gluconeogenic substrate supply has
important implications, since gluconeogenesis is a large component of
Ra in the insulin-deficient state (24). Furthermore, the role of sympathetic drive on Ra could not be completely
delineated, since -adrenergic receptors were unblocked in these
prior studies.
The present study was designed to determine the role of hepatic
adrenergic mechanisms in the stimulation of Ra during
exercise in the poorly controlled diabetic state. For this purpose, we used an - and -hepatic adrenergic receptor blockade technique that is selective to the liver and that produces minimal extrahepatic effects (6) in chronically catheterized alloxan-diabetic dogs.
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METHODS |
Animals and surgical procedures.
Experiments were performed on a total of 12 overnight-fasted mongrel
dogs (mean wt 21.5 ± 0.5 kg) of either sex that had been fed a
standard diet (Pedigree beef dinner and Wayne Lab Blox, 51%
carbohydrate-31% protein-11% fat-7% fiber based on dry wt). The dogs
were housed in a facility that met American Association for the
Accreditation of Laboratory Animal Care guidelines, and the protocols
were approved by the Vanderbilt University Animal Care Committee.
At least 16 days before each experiment, a laparotomy was performed
under general anesthesia (0.04 mg/kg of atropine and 15 mg/kg
pentobarbital sodium presurgery and 1.0% isoflurane inhalation anesthetic during surgery). Silastic sampling catheters were inserted in the carotid artery, portal vein, and hepatic vein as previously described (6). Silastic catheters were also inserted for the infusion
of indocyanine green, [3-3H]glucose, and
[U-14C]alanine according to methods published
previously (27). Last, a Silastic catheter was inserted for the
intraportal infusions of phentolamine and propranolol and the infusion
of catecholamines during the final period of the experiment, as
previously described (6). Ultrasonic transit time flow probes were
fitted and secured to the portal vein and hepatic artery (Transonic
Systems, Ithaca, NY). The knotted catheter ends and flow probe leads
were stored in a subcutaneous pocket in the abdominal region. The
carotid artery catheter was stored in a pocket under the skin of the neck.
Alloxan (BDH Chemicals, Poole, England) was used to induce diabetes
according to methods previously described (7). After glycosuria was
detected, the dogs were treated with regular and isophane pork insulin
(Eli Lilly, Indianapolis, IN) to maintain glycosuria <1 mg/dl. Pork
insulin was used since it does not yield antibody formation for at
least 2 mo, thereby allowing accurate insulin measurements (23). The
last injection of intermediate-acting insulin was given 48 h before
studies, with the last injection of short-acting insulin given 18 h
before study. The regimen of insulin doses used ensures that diabetic
dogs are free of subcutaneous insulin on the day of the study (27).
Beginning 7 days after surgery, dogs were acclimatized to running on a
motorized treadmill. In addition, blood samples were drawn 3 days
before the experiment to determine the leukocyte count and the
hematocrit of the animal. Only animals with a leukocyte count below
18,000/mm3, a hematocrit above 38%, a good appetite
(consumption of daily food ration), and normal stools were used.
All studies were conducted in dogs after an 18-h fast. The free
catheter ends and flow probe leads were accessed through small skin
incisions made under local subcutaneous anesthesia (2% lidocaine; Astra Pharmaceutical, Worcester, MA) in the abdominal and neck regions
the morning of the experiment. The contents of the catheters were then
aspirated and flushed with saline. The exposed catheters were connected
to Silastic tubing that was secured to the back of the dog with
quick-drying glue.
Experimental procedures.
Experiments consisted of a tracer and dye equilibration period
(
150 to 30 min), basal period (30 to 0 min),
moderate exercise period (0-150 min), recovery period
(150-180 min), and catecholamine infusion period (180-210
min). A primed (42 mCi), constant infusion (0.30 mCi/min) of
[3-3H]glucose was initiated at 130 min
and was continued throughout the study. A constant-rate indocyanine
green infusion (0.1 mg · m2 · min1)
and [U-14C]alanine (0.36 mCi/min) was also
started at time (t) = 150 min and was continued
throughout the study. Indocyanine green was used as a backup method of
blood flow measurement if the flow probes did not provide a clear
signal and as confirmation of hepatic vein catheter placement. Two
protocols were performed (Fig. 1). In the
hepatic adrenergic blockade protocol (HAB, n = 6), the - and
-adrenergic receptor blockers phentolamine and propranolol were infused intraportally from 50 to 210 min at rates of 2 and 1 µg · kg1 · min1,
respectively. These infusion rates block hepatic adrenergic receptors
while eliciting minimal extrahepatic effects (6). To test the
effectiveness of the blockade, norepinephrine and epinephrine were
infused at rates of 0.40 and 0.20 ng · kg1 · min1,
respectively, from t = 180-210 min of the study. In the
control protocol (n = 6), animals were handled and prepared
identically except that vehicle alone (saline and ascorbate) was
infused. Catecholamine and arterial plasma glucose data for four of the six control dogs have been published previously (7). Glucagon and
insulin data for five of the six control dogs have also been published
previously (8). Heart rates and blood flows were monitored on-line
throughout the experiments.
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Fig. 1.
Moderate exercise protocol using control and hepatic adrenergic
blockade groups in poorly controlled alloxan-diabetic dogs.
*Epinephrine and norepinephrine were infused into the portal vein at
rates of 0.20 and 0.40 mg · kg1 · min1
from time (t) = 180 to t = 210 min. **Phentolamine and
propranolol were infused at rates of 2 and 1 mg · kg1 · min1,
respectively, from t = 50 to 210 min.
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Blood sample processing.
Plasma glucose concentrations were determined by the glucose oxidase
method using a Beckman glucose analyzer (Beckman Instruments, Fullerton, CA). Plasma samples were prepared, and radioactivity (3H and 14C) was determined as described
previously (27). Whole blood lactate, alanine, and glycerol
concentrations and plasma FFA were determined using previously
established methods (6). Labeled and unlabeled plasma alanine levels
were determined with a short column-ion exchange chromatographic system
that has been described previously (3). Immunoreactive insulin was
measured using a double-antibody procedure (interassay coefficient of
variation of 16%; see Ref. 17). Immunoreactive glucagon (3,500 mol wt) was measured in plasma samples containing 50 ml of 500 KIU/ml Trasylol
(FBA Pharmaceuticals) using a double-antibody system modified from the
method developed by Morgan and Lazarow (17) for insulin. Plasma samples
for norepinephrine and epinephrine were collected as previously
described (6) and analyzed using HPLC (12). The interassay coefficients
of variation using this method were 4 and 6% for norepinephrine and
epinephrine, respectively. Plasma cortisol was measured as previously
described (6) with an interassay coefficient of variation of 6%.
Materials.
[3-3H]glucose (New England Nuclear, Boston, MA)
was used as the glucose tracer (500 Ci/0.005 mg), and
[U-14C]alanine (Amersham, Chicago, IL) was used
as the labeled gluconeogenic precursor (171 mCi/mmol). Glucagon and
125I-glucagon were obtained from Novo-Nordisk Research
Institute (Copenhagen, Denmark). Glucagon and insulin antisera were
obtained from Linco Research (St. Louis, MO), as were standard insulin and 125I-insulin. Enzymes and coenzymes for metabolite
analyses were obtained from Boehringer Mannheim Biochemicals and Sigma Chemical.
Calculations.
Net hepatic lactate uptake (NHLU), alanine uptake (NHAU), glycerol
uptake (NHGlyU), and glucose output were determined according to the
formula HAF × ([A] [H]) + PVF × ([P] [H]), such that [A], [P], and [H] are the arterial,
portal vein, and hepatic vein substrate concentrations, and HAF and PVF
are the hepatic artery and portal vein blood flows. The sign was
reversed for the calculation of NHLU, NHAU, and NHGlyU so that net
uptake would be a positive number. Ra and Rd
were determined by the equations for isotope dilution during a
constant-rate infusion of radioactive glucose ([3-3H]glucose; see Ref. 10).
Hepatic [14C]glucose production was determined
using [3H]glucose in a manner analogous to the
measurement of Ra, with the difference being that the
specific activity was the ratio of plasma
[3H]glucose to plasma
[14C]glucose. Gluconeogenic conversion and the
efficiency of gluconeogenic conversion of alanine and lactate to
glucose were then calculated according to methods previously described
(27). Due to isotope dilution in the liver, the values obtained for
gluconeogenic conversion and efficiency are minimum estimates (13). For
this reason, the [U-14C]alanine gluconeogenic
method cannot quantify gluconeogenesis. Its value rests in the
qualitative assessment of changes relative to basal (4). The
gluconeogenic measurements are described in more detail in previous
publications (4, 27).
Statistical analysis.
Superanova (Abacus Concepts, Berkeley, CA) software installed on a
Macintosh Power PC was used to perform statistical analysis. Statistical comparisons between groups and over time were made using
ANOVA designed to account for repeated measures. Time points were
specifically examined for significance using contrasts solved by
univariate repeated measures. Statistics are reported in Tables 1-3 or Figs. 1-8 for each variable. Data are presented as
means ± SE. Statistical significance was defined as P < 0.05.
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RESULTS |
Arterial insulin, glucagon, and cortisol concentrations
. Glucagon and insulin data for five of the six control dogs
have been published previously (8). The plasma insulin change from
basal was similar in both groups during the exercise and recovery
periods. Although plasma insulin was decreased (P < 0.05) from basal levels in HAB during the blockade test period, insulin increased (P < 0.05) above baseline in controls (Fig.
2). Basal arterial plasma glucagon was
similar in HAB (56 ± 8 pg/ml) and controls (57 ± 9 pg/ml; Fig. 2).
The increase (P < 0.05) in plasma glucagon was similar in HAB
and controls during the exercise and recovery periods. During the
blockade test period, plasma glucagon decreased toward baseline levels
in HAB but remained elevated in controls. Basal plasma cortisol was
similar in HAB (1.4 ± 0.2 mg/ml) and controls (1.2 ± 0.2 mg/ml). The exercise-induced change in cortisol was not different
between groups (Fig. 3).
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Fig. 2.
Exercise-induced changes in arterial insulin and glucagon during the
basal, exercise, recovery, and blockade test periods. Basal values for
insulin and glucagon were 4.8 ± 0.9 mU/ml and 57 ± 9 pg/ml in
controls and 4.0 ± 0.6 mU/ml and 56 ± 7 pg/ml in hepatic adrenergic
blockade (HAB), respectively.  , Change. Data are means ± SE; n = 6 dogs for controls and n = 6 dogs for HAB.
# P < 0.05, difference between basal and exercise period.
* P < 0.05, difference between controls and HAB.
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Fig. 3.
Exercise-induced changes in arterial cortisol during the basal and
exercise periods. Basal values were 1.2 ± 0.2 mg/ml in controls and
1.2 ± 0.3 mg/ml in HAB. Data are means ± SE; n = 6 dogs for
controls and n = 6 dogs for HAB. # P < 0.05, difference between basal and exercise period.
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Arterial epinephrine and norepinephrine concentrations
. Catecholamine values for four of the six control dogs have
been published previously (7). Although the basal arterial plasma
epinephrine was significantly higher in HAB (314 ± 77 pg/ml) compared
with controls (83 ± 17 pg/ml), the exercise-induced increase (P < 0.05) in arterial plasma epinephrine was similar (305 ± 85 pg/ml in HAB and 365 ± 127 pg/ml in controls; Fig.
4). The plasma epinephrine change from
basal was also similar during the recovery and blockade test periods.
Basal arterial plasma norepinephrine was also significantly higher in
HAB (744 ± 134 pg/ml) compared with controls (292 ± 81 pg/ml).
However, plasma norepinephrine increased (P < 0.05) similarly
in HAB (630 ± 85 pg/ml) and controls (619 ± 91 pg/ml) during
exercise (Fig. 4). Likewise, the plasma norepinephrine change from
basal was similar during the recovery and blockade test periods (Fig.
4).
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Fig. 4.
Exercise-induced changes in arterial epinephrine and norepinephrine
during the basal, exercise, recovery, and blockade test periods. Basal
values for epinephrine and norepinephrine were 83 ± 17 and 292 ± 81 pg/ml in controls and 314 ± 77 and 744 ± 134 pg/ml in HAB,
respectively. Data are means ± SE; n = 6 dogs for controls
and n = 6 dogs for HAB. # P < 0.05, difference
between basal and exercise period.
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Arterial glucose concentrations and kinetics
. Although arterial plasma glucose was similar in HAB and
controls during the basal, exercise, and recovery periods, arterial plasma glucose was lower (P < 0.05) in HAB compared with
controls during the blockade test period (Fig.
5). Ra was similar throughout the basal, exercise, and recovery periods. However, Ra was
lower in HAB (8.0 ± 1.0 mg · kg1 · min1)
compared with controls (11.0 ± 1.8 mg · kg1 · min1)
during the blockade test period (Fig. 6).
Rd was similar in both groups throughout the basal,
exercise, recovery, and blockade test periods (Fig. 6).
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Fig. 5.
Arterial glucose during the basal, exercise, recovery, and blockade
test periods. Data are means ± SE; n = 6 dogs for controls
and n = 6 dogs for HAB. * P < 0.05, difference
between controls and HAB.
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Fig. 6.
Endogenous glucose production and glucose utilization during the basal,
exercise, recovery, and blockade test periods. Data are means ± SE;
n = 6 dogs for controls and n = 6 dogs for HAB.
* P < 0.05, difference between controls and HAB.
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Metabolites
. Basal arterial lactate was similar in HAB and controls.
Although arterial lactate was similar in both groups at 50 min of exercise, lactate levels were lower (P < 0.05) in HAB
compared with controls at 150 min of exercise (Table
1). Hepatic fractional lactate extraction
was also lower (P < 0.05) in HAB compared with controls at
150 min of exercise (Table 1). Last, lower levels of arterial lactate
and hepatic fractional lactate extraction corresponded to a reduced
(P < 0.05) NHLU in HAB compared with controls at 150 min of
exercise (Table 1). Arterial alanine, hepatic fractional alanine
extraction, and NHAU were similar throughout the basal and exercise
periods in both groups (Table 1). Arterial glycerol, hepatic fractional
glycerol extraction, and NHGlyU were also similar throughout the basal
and exercise periods (Table 1). Plasma FFA was not different between
groups during the basal and exercise periods (Table
2).
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Table 1.
Arterial lactate, alanine, and glycerol, hepatic fractional lactate,
alanine, and glycerol extraction, and NHLU, NHAU, and NHGlyU during the
basal and exercise periods in control and hepatic adrenergic blockade
diabetic dogs
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Gluconeogenic indexes.
Gluconeogenic conversion from alanine and lactate (expressed as percent
of basal) increased (P < 0.05) twofold by exercise and was
similar in HAB and controls (Fig. 7). The
efficiency of gluconeogenic conversion from alanine and lactate
(expressed as percent of basal) was increased (P < 0.05) by
almost twofold during exercise in both groups (Fig. 7).
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Fig. 7.
Exercise-induced changes in gluconeogenic conversion from alanine and
lactate and the efficiency of gluconeogenic conversion from alanine and
lactate during the basal and exercise periods. Data are means ± SE;
n = 6 dogs for controls and n = 6 dogs for HAB.
# P < 0.05, difference between basal and exercise
period.
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Heart rates and hepatic blood flows.
Heart rates were similar during the basal period and increased
(P < 0.05) similarly with exercise in HAB (204 ± 7 beats/min) and controls (216 ± 13 beats/min; Fig.
8). Portal vein and hepatic artery blood
flows were similar in HAB and controls during the basal and moderate
exercise periods (Table 3).
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Fig. 8.
Heart rates during the basal, exercise, recovery, and blockade test
periods. Data are means ± SE; n = 6 dogs for controls and
n = 6 dogs for HAB. # P < 0.05, difference between
basal and exercise period.
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DISCUSSION |
We have previously shown that nonhepatic splanchnic and hepatic
norepinephrine spillover (index of hepatic sympathetic drive) are
increased in the poorly controlled alloxan-diabetic dog during moderate
exercise in excess of the response in normal healthy dogs (7). In
addition, other studies have suggested that glucose fluxes may be more
sensitive to adrenergic stimulation in diabetes (19-21).
Therefore, it seems reasonable to propose that hepatic adrenergic
mechanisms are a stimulus for exercise-induced increments in
Ra under such conditions. This proposal is consistent with studies which show that peripheral administration of propranolol results in a reduction in Ra during exercise in
depancreatized dogs (2). Although these studies were important in
demonstrating the effectiveness of -adrenergic blockade in the
control of Ra during exercise in the diabetic state, the
regulatory elements by which adrenergic stimulation can mediate
glucoregulation are multifactorial. For example, adrenergic stimulation
may influence the rates of hepatic glycogenolysis and gluconeogenic
parameters through peripheral and hepatic mechanisms. In addition, it
may act through - as well as -adrenergic receptors. The
methodological approach used in the present study allowed us to
selectively determine the importance of direct hepatic adrenergic
stimulation (6) in the control of Ra during exercise in the
poorly controlled diabetic state.
The selective hepatic adrenergic blockade in the present study
prevented the adrenergic stimulation of the liver. The similar increases in Ra in HAB and controls during exercise show
that adrenergic mechanisms acting at the liver are not responsible for
the exercise-induced increment in Ra in the poorly
controlled diabetic state. Although adrenergic mechanisms were not
implicated in the direct stimulation of hepatic glycogenolysis or
gluconeogenesis in the present study, the local delivery of propranolol
and phentolamine largely preserved peripheral stimulatory effects of
the catecholamines on the mobilization of gluconeogenic substrate. Thus
the peripheral action of circulating catecholamines was most likely
sufficient to facilitate exercise-induced changes in gluconeogenic
parameters and contribute to equivalent exercise-induced changes in
Ra in HAB and controls.
It is well recognized that glucagon is critical for the stimulation of
Ra during exercise under healthy (28) and diabetic (30)
conditions. Furthermore, recent studies from our laboratory have
demonstrated an approximately fourfold greater exercise-induced increment in portal vein glucagon in the poorly controlled diabetic state compared with normal dogs (8). Because sympathetic drive to
nonhepatic splanchnic tissue (including pancreas) is elevated during
exercise in the poorly controlled diabetic state (7), increased
sympathetic drive could be important in mediating pancreatic hormone
secretion via adrenergic mechanisms (16, 18). A causal relationship
between exaggerated sympathetic drive and glucagon secretion in the
alloxan-diabetic dogs during exercise are important since glucagon is
probably a major controller of gluconeogenic precursor extraction,
intrahepatic conversion to glucose, and hepatic glycogenolysis under
these conditions (31). Therefore, exaggerated glucagon secretion in the
diabetic state probably contributes to the increase in hepatic
glycogenolysis and the increase in gluconeogenic conversion. This is
supported by studies that show that suppression of glucagon below basal
levels reduces arterial glucose in exercising alloxan-diabetic dogs
(29).
The increased arterial lactate levels in controls resulted in a greater
rate of NHLU in this group. Even though NHLU and hepatic fractional
lactate extraction were greater in controls, gluconeogenic parameters
(alanine and lactate conversion to glucose) increased similarly during
exercise in both groups. Thus the disparity in NHLU in controls and HAB
was insufficient to cause a detectable difference in the gluconeogenic
conversion from alanine and lactate. The difference in NHLU between HAB
and controls would have resulted in a maximum contribution of lactate
to glucose of ~0.25
mg · kg1 · min1,
if all of the lactate consumed by the liver was channeled into glucose.
These results are consistent with studies in lactate-infused (4-fold
basal) dogs in which NHLU but not gluconeogenic parameters were
measured (9).
It is interesting to note that basal arterial epinephrine and
norepinephrine concentrations were elevated in HAB compared with
controls. These results are in agreement with other studies using
"global" - and/or -adrenergic blockade in healthy (11) and
diabetic (22) humans. However, there were no differences in
catecholamines in our previous study using the intraportal blockade
technique in nondiabetic dogs (6). This discrepancy is probably
attributable to increased sympathetic nerve activity in diabetes (7).
Despite the differences in catecholamines during the basal period, the
exercise-induced increments in the catecholamines were similar in both
groups. Therefore, even though the absolute catecholamine levels were
higher in HAB, the hepatic adrenergic blockade has been shown to
inhibit hepatic Ra even under conditions in which portal
epinephrine and norepinephrine values are ~10-fold higher than those
in HAB (5). Furthermore, the inhibition of changes in Ra
during the blockade test period in HAB also substantiates the
effectiveness of the blockade, even at high catecholamine levels.
The completeness of the blockade is supported by the attenuation of
Ra during the portal vein infusion of catecholamines in HAB, whereas Ra was increased in controls. The selectivity
of the blockade is exemplified by similar glycerol and FFA responses in
both groups, since systemic -adrenergic blockade of adipose tissue
normally attenuates glycerol and FFA responses to exercise (14). In
addition, similar heart rate responses in both groups also provide
evidence for the selectivity of the hepatic adrenergic blockade.
Studies show that peripheral -adrenergic blockade can reduce the
exercise-induced heart rate response by 60% (1). The dramatic
reduction of the systemic effects of the adrenergic blockers due to
portal vein infusion is attributable to the marked reduction in the
infusion rate needed to block hepatic adrenergic receptors compared
with the infusion rate needed when using peripheral infusion, as well
as their efficient extraction by the liver (5).
In summary, the novel approach of the present study, whereby the
proposed direct effects of the catecholamines could be distinguished from their indirect effects on the liver (mobilization of gluconeogenic precursors and FFA), shows that direct adrenergic stimulation of
Ra is not an important part of the response to exercise in the diabetic state. These results are consistent with other studies from our laboratory in which HAB did not attenuate Ra
during heavy exercise (6), another condition in which adrenergic drive
to the liver is high.
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ACKNOWLEDGEMENTS |
We are grateful to Deanna Bracy, Eric Allen, Pamela Venson, and
Wanda Snead for excellent technical assistance.
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FOOTNOTES |
This research was supported by National Institute of Diabetes and
Digestive and Kidney Diseases Grant R01-DK-50277 and Diabetes Research
and Training Grant 5-P60-DK-20593. R. H. Coker was a recipient of a
Postdoctoral Fellowship Award from the Juvenile Diabetes Foundation International.
Part of this work was presented at the 59th Annual Meeting of the
American Diabetes Association, San Diego, CA, in June, 1999.
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: R. H. Coker,
Dept. of Exercise Science, Univ. of Mississippi, University, MS 38677 (E-mail address: rhcoker{at}olemiss.edu).
Received 13 July 1999; accepted in final form 12 October 1999.
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