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Exercise Physiology and Metabolism Laboratory, Department of Kinesiology and Health Education, University of Texas at Austin, Austin, Texas 78712
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We recently demonstrated that epinephrine could inhibit the activation by insulin of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase (PI3-kinase) in skeletal muscle (Hunt DG, Zhenping D, and Ivy JL. J Appl Physiol 92: 1285-1292, 2002). Activation of PI3-kinase is recognized as an essential step in the activation of muscle glucose transport by insulin. We therefore investigated the effect of epinephrine on insulin-stimulated glucose transport in both fast-twitch (epitrochlearis) and slow-twitch (soleus) muscle of the rat by using an isolated muscle preparation. Glucose transport was significantly increased in the epitrochlearis and soleus when incubated in 50 and 100 µU/ml insulin, respectively. Activation of glucose transport by 50 µU/ml insulin was inhibited by 24 nM epinephrine in both muscle types. This inhibition of glucose transport by epinephrine was accompanied by suppression of IRS-1-associated PI3-kinase activation. However, when muscles were incubated in 100 µU/ml insulin, 24 nM epinephrine was unable to inhibit IRS-1-associated PI3-kinase activation or glucose transport. Even when epinephrine concentration was increased to 500 nM, no attenuating effect was observed on glucose transport. Results of this study indicate that epinephrine is capable of inhibiting glucose transport activated by a moderate, but not a high, physiological insulin concentration. The inhibition of glucose transport by epinephrine appears to involve the inhibition of IRS-1-associated PI3-kinase activation.
phosphatidylinositol 3-kinase; 
-adrenergic receptor; insulin
receptor; insulin receptor substrate-1
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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GLUCOSE TRANSPORT IS THE
MOVEMENT of glucose across the plasma membrane, whereas glucose
uptake is the transport and phosphorylation of glucose by hexokinase
that results in its clearance from the surrounding medium
(13). Insulin binding to its receptor activates several intracellular signaling proteins, which ultimately leads to an
increase in glucose transport and uptake (28, 29). It is
generally believed that glucose transport is the rate-limiting step in
glucose uptake and disposal. However, epinephrine acting via
-adrenergic receptors can shift the rate-limiting step from glucose
transport to glucose uptake by inhibiting hexokinase and glucose
phosphorylation (1, 4, 14, 18, 21).
In a previous study from our laboratory (11), epinephrine was shown to attenuate the increase in muscle glucose uptake elicited by a moderate physiological insulin concentration. The results suggested that epinephrine attenuated glucose uptake by reducing the rate of glucose phosphorylation. However, epinephrine also blocked insulin-stimulated insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase (PI3-kinase) activity. Activation of PI3-kinase is an essential step for insulin-stimulated glucose transport (3, 5, 29). It is therefore possible that the reduction in insulin-stimulated glucose uptake by epinephrine we previously observed was due to an attenuation in glucose transport rather than or in addition to an inhibition of glucose phosphorylation. The purpose of the present study, therefore, was to investigate the effects of epinephrine on insulin-stimulated PI3-kinase activation and glucose transport in skeletal muscle. The findings of this study indicate that epinephrine can inhibit insulin-stimulated muscle glucose transport, but only when insulin is within a low to moderate physiological range.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals and muscle preparation. Harlan Sprague-Dawley rats (n = 40) between 110-120 g were randomly assigned to the following three groups: basal, insulin, insulin-epinephrine. All animals were obtained from and housed in the Animal Resource Center, University of Texas, Austin, TX. The temperature of the animal room was maintained at 21°C, and a 12:12-h light-dark cycle was set. All procedures were approved by the Animal Care and Use Committee of the University of Texas and conformed to the guidelines for the use of laboratory animals published by the US Department of Health and Human Services.
Rats were anesthetized after an 8-h fast via an intraperitoneal injection of pentobarbital sodium (6.5 mg/100 g body wt), and the epitrochlearis (fast twitch) and soleus (slow twitch) muscles were then excised. The soleus was separated into strips weighing ~15 mg and, with the epitrochlearis, was used to assess glucose transport and PI3-kinase activity after in vitro incubation.Muscle incubation. After isolation, epitrochlearis and soleus muscles were individually preincubated for 50 min in 1.5 ml of continuously gassed (95% O2-5% CO2) Krebs-Henseleit bicarbonate buffer containing 0.1% BSA, 32 mM mannitol, and 8 mM glucose. After preincubation, muscles were washed for 10 min in fresh buffer (1.5 ml) containing 0.1% BSA and 40 mM mannitol. Muscles were then incubated for 15 min in fresh buffer (1.5 ml) containing 0.1% BSA, 2 mM pyruvate, 38 mM mannitol, and 0.5 mg/ml ascorbic acid with either 0 insulin, 50 µU/ml insulin (Eli Lilly, Indianapolis, IN), or 50 µU/ml insulin plus 24 nM epinephrine (Sigma Chemical, St. Louis, MO). Next, the muscles were transferred to fresh buffer, and glucose transport was measured after a 15-min incubation in the presence of 0.1% BSA, 0.5 mg/ml ascorbic acid, 2 mM pyruvate, 6 mM 3-O-methyl-glucose (3-OMG), 280 µCi/mmol 3H-labeled 3-OMG (Dupont NEN, Boston, MA), 32 mM mannitol, 10 µCi/mmol [14C]-mannitol (ICN Pharmaceuticals, Costa Mesa, CA), and the appropriate hormone concentration. For muscles in which IRS-1-associated PI3-kinase activity was to be measured, all radioactive isotopes were absent from the incubation medium. All incubations occurred at 29°C. After the last incubation period, muscles were blotted and freeze clamped with Wollenberg tongs cooled in liquid nitrogen.
The ability of epinephrine (24 and 500 nM) to attenuate skeletal muscle glucose transport was also evaluated in the presence of 100 µU/ml insulin. Incubation procedures were identical to those described when 0 and 50 µU/ml insulin concentrations were evaluated with one exception. The initial 15-min incubation after the 10-min washout was eliminated. Thus glucose transport and PI3-kinase activity were assessed after 15 min of hormone exposure rather than after 30 min. The rationale for reducing the exposure time was based on recent findings by Song et al. (24). They demonstrated that PI3-kinase activity peaked at 6 min and then declined to basal values after exposure to a maximal insulin concentration in both the epitrochlearis and soleus muscles. In a previous study from our laboratory, we observed that PI3-kinase activity in the epitrochlearis and soleus muscles was maximal between 30 and 40 min of incubation with 50 µU/ml insulin (11). Thus, with an insulin concentration of 100 µU/ml, we reasoned that peak PI3-kinase activity would occur earlier than with insulin concentration of 50 µU/ml. Therefore, we reduced the exposure time to 15 min to ensure detection of an effect of epinephrine on insulin-stimulated PI3-kinase activity.Muscle processing for determination of glucose transport. Glucose transport was estimated by determining the incorporation rate of 3H-labeled 3-OMG into skeletal muscle. 3-OMG is a glucose analog that has transport rates similar to glucose but is not phosphorylated by hexokinase and provides a good estimate of the rate of glucose transport in skeletal muscle. Incubated muscles were weighed and dissolved in 1 M KOH for 15 min at 60°C. Dissolved samples were then neutralized with 1 M HCl, and 0.3 ml of the supernatant was added to 6 ml of Biosafe II scintillation fluid (Research Products International, Mount Prospect, IL). Samples were counted for 3H and 14C in a LS-6000 liquid scintillation spectrophotometer (Beckman, Fullerton, CA).
IRS-1-associated PI3-kinase activity determination. For PI3-kinase activity, muscle samples were homogenized, and aliquots of the homogenate were diluted to 2 µg/µl of protein in homogenization buffer. Samples were then immunoprecipitated by incubating for 2 h on ice with 2 µg of anti-IRS-1 antibody (Upstate Biotechnology, Lake Placid, NY). Protein A-Sepharose beads (Sigma Chemical) were added to the immunoprecipitation reaction, and incubation was continued for another 90 min at 4°C with rotation. The protein A- Sepharose beads-antibody complex was precipitated by centrifugation (5 min at 20,400 g).
Immunoprecipitates were washed successively with 1) PBS containing 10% (octylphenoxy)polyethoxyethanol, 100 mM Na3VO4, and 1 M dithiothreitol; 2) 1 M Tris · HCl (pH 7.5), 2 M LiCl2, 100 mM Na3VO4, and 1 M dithiothreitol; and 3) 1 M Tris · HCl (pH 7.5), 5 M NaCl, 10 mM EDTA, 100 mM Na3VO4, and 1 M dithiothreitol. Washing was done one time each with buffers 1 and 2 and twice with buffer 3. Packed beads were suspended, and 20 µl of phosphotidylinositol (Avanti Polar Lipids, Alabaster, AL) were dissolved in 4× HEPES and distilled H2O for a final concentration of 10 mg/ml. The kinase reaction was started by adding 10 µl of 10 mM ATP, 4× HEPES buffer, 0.4 M MgCl2, and 0.16 µCi/µl [
-32P]ATP
(Dupont). The reaction was incubated at room temperature with vigorous
shaking and was terminated by adding 15 µl of 4 N HCl and 130 µl of
MeOH-CHCl3 (1:1, vol/vol). After brief centrifugation, 20 µl of the organic solvent layer were spotted onto a thin-layer chromatography plate (Silica gel 60, Whatman, Hillsboro, OR) that had
been activated with potassium oxalate. After phosphoinositides in
running solvent
(CHCl3-MeOH-H2O-NH4OH,
60:47:11:3.2, vol/vol/vol/vol) were separated, plates were dried and
exposed. Spots were scraped from the plates and counted for
32P in 6 ml of Biosafe II scintillation fluid in a
scintillation counter.
Statistical analysis. A one-way analysis of variance among experimental groups was performed on all variables. Fisher's protected least significance test was utilized to distinguish significant differences between groups. A level of P < 0.05 was set for significance for all test, and all values are expressed as means ± SE.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In the isolated epitrochlearis and soleus muscles, an insulin
concentration of 50 µU/ml increased glucose transport 53 and 138%
above basal, respectively (Fig. 1, A and
B). An insulin concentration of 100 µU/ml increased glucose transport 220% above basal in the epitrochlearis and 378% above basal in the soleus muscle (Fig. 2,
A and B).
Epinephrine (24 nM) inhibited glucose transport in the presence of 50 µU/ml insulin in both the epitrochlearis and soleus muscles. However,
when muscles were incubated in 100 µU/ml insulin, neither 24 nor 500 nM epinephrine had a significant effect on glucose transport.
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An insulin concentration of 50 µU/ml increased IRS-1-associated
PI3-kinase activity in the epitrochlearis by 68% and in the soleus by
106% above basal (Fig. 3, A and
B). An insulin concentration of 100 µU/ml significantly increased IRS-1-associated PI3-kinase activity in the epitrochlearis by 72% and in the soleus by 63% (Fig.
4, A and B).
Activation of IRS-1-associated PI3-kinase by 50 µU/ml insulin was
inhibited by 24 nM epinephrine in both the epitrochlearis and soleus
muscles. In the presence of 100 µU/ml insulin, neither 24 nor 500 nM
epinephrine had an effect on insulin-stimulated IRS-1-associated
PI3-kinase activity.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Epinephrine is effective in attenuating glucose uptake stimulated by a physiological concentration of insulin (11, 12, 14, 21). It is generally accepted that epinephrine attenuates glucose uptake by inhibiting hexokinase and glucose phosphorylation (1, 4, 18, 21, 23). However, we recently found that, under certain in vitro conditions, this attenuation in insulin-stimulated glucose uptake can also coincide with a reduction in IRS-1-associated PI3-kinase activity (11, 12). Evidence suggests that the activation of PI3-kinase is necessary for the stimulation of glucose transport by insulin (3, 5, 20). Thus we hypothesized that inhibition of glucose uptake by epinephrine in the presence of a moderate physiological insulin concentration may be due to the inhibition of glucose transport rather than to a step distal to transport.
In the present study, 50 and 100 µU/ml insulin increased IRS-1-associated PI3-kinase activity and glucose transport in the epitrochlearis and soleus muscles. Furthermore, 24 nM epinephrine was found to block activation of IRS-1-associated PI3-kinase by 50 µU/ml, and this coincided with a reduction in insulin-stimulated glucose transport. These results are in agreement with earlier studies in which insulin-stimulated glucose transport was found to require the activation of PI3-kinase (3, 5, 20). In studies by Cheatham et al. (3), Clarke et al. (5), and Lee et al. (20) in which the fungal metabolite wortmannin was used to block the activation of PI3-kinase, a corresponding inhibition in insulin-stimulated glucose transport was reported. The results of the present study, therefore, suggest that a physiological epinephrine concentration can reduce insulin-stimulated muscle glucose uptake by inhibiting glucose transport rather than by inhibiting hexokinase and glucose phosphorylation. However, this effect of epinephrine appears to be insulin-concentration specific because epinephrine had no attenuating effect on IRS-1-associated PI3-kinase activity or glucose transport activated by 100 µU/ml insulin. Even when epinephrine was increased from 24 to 500 nM, glucose transport was unabated in the presence of 100 µU/ml insulin. Therefore, the ability of epinephrine to attenuate insulin-stimulated glucose uptake by inhibiting transport appears to be limited to insulin concentrations in the low to moderate physiological range.
Previous research strongly supports the concept that epinephrine has no
effect on insulin-stimulated glucose transport. In the classic studies
of Kipnis and colleagues (18, 19), it was demonstrated
that epinephrine increased the intracellular free glucose concentration
of skeletal muscle. Furthermore, epinephrine was found to inhibit
maximal insulin-stimulated 2-deoxyglucose phosphorylation by 40%,
whereas the intracellular concentration of 2-deoxyglucose increased
proportionately. From these results, it was concluded that epinephrine
inhibits insulin-stimulated glucose uptake in skeletal muscle by
inhibiting hexokinase activity. The first study to directly assess the
effect of epinephrine on insulin-stimulated glucose transport was
conducted by Chiasson et al. (4). Using the rat hindlimb
perfusion technique, they found that 100 nM epinephrine had no effect
on 3-OMG transport activated by 1,000 µU/ml insulin but that it was
effective in inhibiting the phosphorylation of 2-deoxyglucose. In
studies that followed, Lee et al. (21) and Pittner et al.
(23) found that even when epinephrine concentration was
increased to 1,000 nM, it had no effect on glucose transport activated
by 
1,000 µU/ml insulin. In addition, Lee et al. (21)
demonstrated that 1,000 nM epinephrine had no effect on glucose
transport in the presence of 60 µU/ml insulin. The one commonality
among these studies, aside from the study by Lee et al.
(21), is that a pharmacological concentration of insulin
was utilized.
In the present study, 24 nM epinephrine had no effect on glucose
transport activated by a high physiological concentration of insulin
(100 µU/ml), which corroborates the findings of earlier studies.
However, when a moderate physiological insulin concentration of 50 µU/ml was utilized, an inhibition of glucose transport was observed.
We cannot at this time reconcile the difference in results between our
findings and those of Lee et al. (21). Possibly, in the
study by Lee et al., prior exposure of muscle to epinephrine caused
downregulation of -adrenergic receptors and reduced the efficacy of
the epinephrine response. Regardless, our finding that epinephrine can
inhibit insulin-stimulated glucose transport is not unique. Han and
Bonen (9) reported that insulin-stimulated glucose
transport in the three basic muscle fiber types of the rat could be
inhibited by a physiological epinephrine concentration.
Under certain circumstances, it is likely that a coordinated control of
muscle glucose transport by insulin and epinephrine is required to
achieve the most desirable physiological response. Recent studies have
demonstrated that epinephrine or agents that increase cAMP can regulate
the insulin signaling pathway by reducing tyrosine kinase activity,
IRS-1 phosphorylation, and PI3-kinase activity (11, 25,
26). Likewise, insulin-receptor activation can also lead to a
reduction in -adrenergic receptor function and adenylyl cyclase
activity (8, 17). These results suggest that cross talk
between these two signaling pathways may be a mode by which insulin and
epinephrine regulate the opposing signaling pathway to control glucose
transport. Therefore, it is possible that when the -adrenergic
signaling pathway has the greater level of receptor activation it will
override the insulin signaling pathway, and when the insulin signaling
pathway reaches a certain level of activation it will override the
-adrenergic signaling pathway. It is also possible that under
elevated insulin conditions, glucose transport can be activated via an
alternative pathway that is not influenced by -adrenergic activation.
There are several conditions when the modulating effects of epinephrine
on insulin-stimulated glucose transport could be important, such as
during exercise. Like insulin, contraction also increases skeletal
muscle glucose transport (6, 12, 22). In combination, insulin and contraction produce a clear additive effect on glucose transport (6, 12, 22). During exercise when blood glucose starts to decline, increased sympathetic activity increases plasma epinephrine levels and lowers plasma insulin levels (27).
Although plasma insulin levels decrease during exercise, there is,
however, an increase in insulin exposure at the active tissue due to an increase in muscle blood flow. Thus a part of the increase in glucose
transport during exercise can be attributed to the action of insulin.
Blockage of the action of epinephrine with the use of -adrenergic
blockers can result in rapid, exercise-induced hypoglycemia (7,
10). This hypoglycemic state induced by -blockade is due to
an increase in glucose utilization by skeletal muscle (2, 12, 15,
16). In a previous study from our laboratory (12),
24 nM epinephrine reduced IRS-1-associated PI3-kinase activity and the
additive effect of insulin and contraction on glucose uptake. The
reduction in insulin/contraction-stimulated glucose uptake resulted in
a glucose uptake rate similar to contraction alone. The present results
suggest that epinephrine may play a significant role in regulating
muscle glucose uptake during exercise by modulating insulin-stimulated
glucose transport as well as by inhibition of hexokinase. Such a
strategy would limit blood glucose utilization without excessive
accumulation of intracellular free glucose; a response that could occur
if inhibition of hexokinase were the only mechanism by which
epinephrine limited glucose uptake.
In summary, the present study demonstrates that epinephrine is capable of modulating glucose transport activated by insulin in the low to moderate physiological range. This could represent a significant means by which epinephrine regulates glucose utilization in the postabsorptive state and during exercise to prevent hypoglycemia, while also protecting the cell against excessive accumulation of intracellular free glucose.
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ACKNOWLEDGEMENTS |
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We are grateful for the excellent technical assistance provided by Zhenping Ding.
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. L. Ivy, Dept. of Kinesiology and Health Education, Bellmont Hall 222, Univ. of Texas at Austin, Austin, TX 78712 (E-mail: johnivy{at}mail.utexas.edu).
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.
August 2, 2002;10.1152/japplphysiol.00445.2002
Received 17 May 2002; accepted in final form 29 July 2002.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Significantly different from insulin
(P < 0.05).
