Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1
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ABSTRACT |
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We examined the effects of epinephrine (25, 50, and 150 nM) on 1) basal and
insulin-stimulated 3-O-methylglucose
(3-MG) transport in perfused rat muscles and
2) GLUT-4 in skeletal muscle plasma membranes. Insulin increased glucose transport 330-600% in three types of skeletal muscle [white (WG) and red (RG) gastrocnemius and soleus (SOL)]. Glucose transport was also increased by
epinephrine (22-48%) in these muscles
(P < 0.05). In contrast, the
insulin-stimulated 3-MG transport was reduced by epinephrine in all
three types of muscles; maximal reductions were observed at 25 nM
epinephrine in WG (25%) and RG (
32.5%). A
dose-dependent decrease occurred in SOL (
27% at 25 nM;
55% at 150 nM, P < 0.05).
Insulin (20 mU/ml) and epinephrine (150 nM) each translocated GLUT-4 to
the plasma membrane, and no differences in translocation were observed between insulin and epinephrine (P > 0.05). In addition, epinephrine did not inhibit insulin-stimulated
GLUT-4 translocation, and the combined epinephrine and insulin effects
on GLUT-4 translocation were not additive. The increase in surface
GLUT-4 was associated with increases in muscle cAMP concentrations, but
only when epinephrine alone was present. No relationship was evident
between muscle cAMP concentrations and surface GLUT-4 in the combined
epinephrine and insulin-stimulated muscles. These studies indicate that
epinephrine can translocate GLUT-4 while at the same time increasing
glucose transport when insulin is absent, or can inhibit glucose
transport when insulin is present.
soleus; red gastrocnemius; white gastrocnemius; adenosine 3',5'-cyclic monophosphate; perfusion
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INTRODUCTION |
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IT IS GENERALLY BELIEVED that glucose transport is the rate-limiting step in glucose utilization in muscle (29). To increase glucose transport in this tissue, the glucose transporter GLUT-4 is translocated from intracellular pool(s) to the surface of the muscle by insulin and exercise, albeit by different signaling pathways that remain largely unknown (2, 3, 14, 33, 46, 50). Some studies have associated all changes in glucose transport directly with the appearance of GLUT-4 at the surface of the cell (32, 33, 49) or to changes in accessibility of glucose to the cell surface GLUT-4 transporter (44). However, a number of studies have also presented evidence to indicate that glucose transport can be altered as a result of changes in the activity of the surface GLUT-4 (1, 13, 16, 27, 28).
Catecholamines can have profound effects on glucose transport in
adipocytes, heart, and skeletal muscle. In adipocytes the -adrenergic agonist isoproterenol stimulates both GLUT-4
translocation and glucose transport at low concentrations (10-25
nM) and inhibits glucose transport at high concentrations (1 µM) (26,
34) because of an inhibition of the transport activity of surface
GLUT-4 (34). cAMP has been implicated in this process, because
dibutyryl-cAMP (DBcAMP) increased glucose transport in adipocytes at
low concentrations (10 µM) and inhibited glucose transport to below
basal transport rates with high concentrations (1,000 µM) (28, 34).
In addition, insulin and DBcAMP (1,000 µM) stimulated GLUT-4
translocation additively, but the insulin-stimulated glucose transport
was reduced (28). In contrast, in cardiac myocytes,
-adrenergic
stimulation failed to increase glucose transport, whereas
-adrenergic stimulation of glucose transport was increased
because of a recruitment of GLUT-4 to the cell surface (13); however,
this did not involve a cAMP-dependent mechanism (12). In skeletal
muscle, epinephrine (24 nM) increased basal glucose uptake (43), but
much higher concentrations of epinephrine (>60 nM) increased surface
GLUT-4 while concurrently lowering glucose transport (1). Thus, in skeletal muscles, epinephrine also appears to exhibit a biphasic effect
on glucose transport, possibly by altering the activity of surface
GLUT-4 transporters.
The effects of epinephrine on glucose transport and GLUT-4
translocation may be muscle fiber specific. Muscles rich in oxidative fibers appear to have a greater density of
2-adrenergic receptors (>90%
2 receptors) than muscles rich
in glycolytic fibers (23, 48). Oxidative muscles also have considerably
more GLUT-4 transporters than glycolytic muscles (18, 19, 36),
resulting in a greater increase in insulin-stimulated glucose transport
in oxidative muscles (18, 19, 36). When these observations are
considered together, it is possible that the inhibitory effects of
epinephrine on glucose transport are greater in oxidative than in
glycolytic muscles. Moreover, by examining the independent and combined
effects of insulin and epinephrine on skeletal muscle
3-O-methylglucose (3-MG) transport and
plasma membrane GLUT-4 content, it is possible to determine whether
epinephrine alters 1) the activity
of GLUT-4 or 2) the insulin-induced
GLUT-4 translocation. Therefore, we examined in three types of rat
skeletal muscles [soleus (SOL), red gastrocnemius (RG), and white
gastrocnemius (WG)] 1) the
effects of epinephrine on basal and insulin-stimulated 3-MG transport and 2) the independent and
concomitant effects of epinephrine and insulin on GLUT-4 content in
skeletal muscle plasma membranes.
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METHODS |
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Hindquarter perfusion. Male Sprague-Dawley rats weighing about 280 g were used in the present experiments. Ethical approval for this work was obtained from the committee on animal care at the University of Waterloo. Rats were anesthetized with intraperitoneal injection of pentobarbital sodium (65 mg/kg body wt). They were surgically prepared for hindquarter perfusion as we have previously described (19). The gassed perfusate (pH 7.45, 95% O2-5% CO2) was a glucose-free medium containing Krebs-Henseleit solution, bovine erythrocytes (obtained from a local abattoir 1-2 days before perfusion) at a hematocrit of 30%, 0.15 mM pyruvate, and 4% BSA. The first 25 ml of the perfusate that passed through the preparation were discarded, and then the medium was recirculated at a flow of 12.5 ml/min.
Glucose transport. Determinations of glucose transport under basal and insulin-stimulated conditions were performed as described previously (19, 40). Briefly, hindquarters were preperfused for 15 min, and then epinephrine at various concentrations (0, 25, 50, and 150 nM) was added for 25 min of perfusion. In other experiments in which we examined the combined effects of epinephrine and insulin, a 15-min preperfusion period was used again; during the next 25 min, epinephrine (0, 25, and 150 nM) was present for the first 10 min and for the last 15 min both epinephrine (0, 25, and 150 nM) and insulin (20 mU/ml) were present together. Insulin-stimulated (20 mU/ml) glucose transport was determined while the hormone was present during the last 15 min of the experiments.
Glucose transport was measured using 8 µCi of 3-O-methyl-D-[3H]glucose (3-[3H]MG), together with unlabeled 3-MG, to attain a final near-saturating concentration of 40 mM (40). Extracellular space determination was determined with 16 µCi of [14C]mannitol. At the end of the perfusion period, perfusate samples and muscle samples from the superficial part of the gastrocnemius muscle [WG; consisting mainly of fast-twitch glycolytic (type IIb) fibers], the deep part of the medial head of the gastrocnemius muscle [RG; consisting mainly of fast-twitch oxidative (type IIa) fibers], and SOL [consisting mainly of slow-twitch oxidative (type I) fibers] (1) were collected. Glucose transport, corrected for extracellular space, was expressed as micromoles per gram of muscle tissue per 5 min, as we have done previously (18, 19).Membrane preparation. Hindquarters were perfused with epinephrine (25 and 150 nM) in the absence of insulin and in the presence of maximal insulin (20 mU/ml) as described in Glucose transport. Because the RG muscles were highly responsive to epinephrine and insulin, plasma membranes were prepared only from these muscles. Moreover, because the GLUT-4 located on the surface of the muscle cell promotes glucose transport, we measured GLUT-4 only in the plasma membranes. RG muscles were removed, trimmed in ice-cold saline, and freeze-clamped in liquid N2 for later membrane isolation. Membranes were prepared using a modification (21) of the procedures initially described by Klip et al. (30). Potassium-stimulated p-nitrophenylphosphatase activity (K+-pNPPase) was assayed in muscle homogenates and plasma membranes as described by Ploug et al. (42). With this measure, the purity of the plasma membrane fractions over the homogenate was increased 17.5 times (P < 0.05) (data not shown). This compares favorably with skeletal muscle plasma membrane preparations published elsewhere (17).
GLUT-4 measurement in plasma membranes. The amount of GLUT-4 protein in muscle plasma membranes of various treatment groups was determined with Western blotting as we have previously reported (25), by use of a commercially available GLUT-4 polyclonal antibody (East Acres Biologicals). An enhanced chemiluminescence detection procedure (ECL, Amersham) was used to visualize the GLUT-4 protein. The quantification of GLUT-4 was carried out by using a scanner (Abaton) and a Macintosh LC computer with appropriate software (Scan Analysis, Biosoft, Cambridge, UK).
cAMP determination. cAMP was determined as described elsewhere (41). Briefly, cAMP was extracted from frozen muscle homogenized in 10 volumes of 7% trichloroacetic acid. The precipitate was removed by centrifugation, and the supernatant was washed five times with 5 volumes of water saturated with diethyl ether. The remaining aqueous extract was lyophilized and dissolved in 50 mM Tris buffer, pH 7.5, containing 4 mM EDTA. Determination of the cAMP concentrations was performed with a [3H]cAMP protein binding assay kit (Amersham, Oakville, ON, Canada).
Statistical analyses. Analyses of variance were used to compare the effects of epinephrine, insulin, and insulin plus epinephrine on glucose transport, GLUT-4 translocation, and cAMP. We also transformed the cAMP data to percentage values of control conditions (i.e., when muscles were perfused without either epinephrine or insulin). This condition was defined as 100%, and then the cAMP data were recalculated as a percentage relative to the mean control. Data in these groups were then analyzed with ANOVA. This then permitted us to examine changes in 3-MG transport and plasma membrane GLUT-4 in relation to cAMP. All data are expressed as means ± SE.
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RESULTS |
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Basal and insulin-stimulated 3-MG glucose transport. The highest basal 3-MG transport rate was observed in the RG, in which transport was slightly (+15%) but consistently higher than in SOL (P < 0.05). Basal 3-MG transport was 46% lower in WG than in RG (P < 0.05) (Fig. 1).
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Effects of epinephrine on 3-MG glucose transport.
Epinephrine increased glucose transport, compared with basal transport
rates, in both RG and WG muscles (Fig. 2,
P < 0.05). 3-MG transport was
maximally stimulated by 25 nM of epinephrine (Fig. 2), because
transport rates did not differ among any of the epinephrine
concentrations used in this study (P > 0.05). When all epinephrine concentrations used are taken into
account, 3-MG transport was increased over basal transport rates by
+32% in WG (P < 0.05), by +48% in
SOL (P < 0.05), and by +22% in RG (P < 0.05). The absolute increases
were greater in the SOL ( = +0.28 ± 0.05 µmol · g
1 · 5 min
1) than in either the
RG (
= +0.14 ± 0.03 µmol · g
1 · 5 min
1)
(P < 0.05) and WG (
= +0.16 ± 0.03 µmol · g
1 · 5 min
1)
(P < 0.05). These slight absolute
differences between RG and WG were not significant
(P > 0.05).
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Effects of epinephrine on insulin-stimulated glucose transport.
Epinephrine decreased the insulin-stimulated 3-MG transport in all
three muscles (Fig. 3,
P < 0.05). In WG and RG the largest decrease in 3-MG transport occurred at an epinephrine concentration of
25 nM (P < 0.05; WG: =
0.41 ± 0.18 µmol · g
1 · 5 min
1 or
25 ± 11.5%; RG:
=
1.05 ± 0.36 µmol · g
1 · 5 min
1 or
32.5 ± 11.2%). No further decreases in insulin-stimulated 3-MG transport were
observed in either WG or RG at 150 nM epinephrine. In contrast, in the
SOL there was a marked decrease in insulin-stimulated 3-MG transport at
the low epinephrine concentration (25 nM)
(P < 0.05;
=
0.95 ± 0.10 µmol · g
1 · 5 min
1 or
26.9 ± 4.5%), and insulin-stimulated 3-MG transport was lowered even further
with 150 nM epinephrine (P < 0.05;
=
1.99 ± 0.05 µmol · g
1 · 5 min
1 or
55.1 ± 1.4%). At the highest concentration of epinephrine (150 nM) the
absolute 3-MG transport decrements in RG and SOL were greater than in
WG (P < 0.05).
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Effects of insulin and epinephrine on plasma membrane GLUT-4. For the studies of plasma membrane GLUT-4, we used only RG muscles. These muscles have a high concentration of GLUT-4 (18, 19, 36), and this muscle was highly responsive to epinephrine (Figs. 2 and 3). At the same time RG muscles can also provide sufficient tissue (700 mg) to obtain plasma membranes.
Insulin increased the appearance of GLUT-4 in the plasma membranes (Fig. 4, P < 0.05). Epinephrine also increased GLUT-4 in the plasma membrane at both low (25 nM; P < 0.05) and high epinephrine concentrations (150 nM; P < 0.05) (Fig. 4). The GLUT-4 increase in the plasma membrane induced by 25 nM epinephrine was somewhat smaller (P < 0.05) than that provoked by maximal concentrations of insulin (Fig. 4). Combining insulin and epinephrine (25 nM) resulted in a greater plasma membrane GLUT-4 concentration than when only epinephrine (25 nM) was present (Fig. 4, P < 0.05). At the higher epinephrine concentration (150 nM), there was no difference in the increase in plasma membrane GLUT-4 compared with the GLUT-4 increase provoked by maximally stimulating levels of insulin (20 mU/ml), either alone or in the presence of 150 nM epinephrine (P > 0.05; Fig. 4). Combining epinephrine (either 25 or 150 nM) and insulin (20 mU/ml) did not increase plasma membrane GLUT-4 in an additive manner (P > 0.05) compared with the increase in GLUT-4 provoked by insulin alone (Fig. 4).
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Effects of insulin and epinephrine on muscle cAMP.
The cAMP concentrations were increased over basal levels when
epinephrine was perfused through the muscles [+27% at 25 nM (P < 0.05); +61% at 150 nM
(P < 0.05; Fig.
5)]. The increase at 150 nM was
greater than at 25 nM (P < 0.05).
When insulin alone was administered, the cAMP concentrations decreased
sharply (55%) (P < 0.05, Fig. 5). However, when epinephrine and insulin were both present, large
increases in cAMP were observed (P < 0.05). However, the cAMP concentrations in the presence of insulin were somewhat lower at 25 nM epinephrine (
9.5%;
P < 0.05) and 150 nM
epinephrine (
16%; P < 0.05)
than when only epinephrine was present in the perfusate (Fig. 5).
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Comparisons of 3-MG transport, plasma membrane GLUT-4, and cAMP. Both insulin and epinephrine increased plasma membrane GLUT-4 compared with GLUT-4 found in the plasma membranes under basal conditions (P < 0.05; Fig. 4). Despite the similar increases in surface GLUT-4 provoked independently by epinephrine (150 nM) and insulin (20 mU/ml) and by epinephrine (150 nM) + insulin (20 mU/ml), there were very marked differences in 3-MG transport among these treatments. Epinephrine alone increased 3-MG transport only slightly (approximately +20%; P > 0.05; Fig. 2), whereas insulin increased 3-MG transport almost 25 times more (+500%). However, in the epinephrine (150 nM) + insulin (20 mU/ml) treatment, the 3-MG transport was sharply reduced (~50%) compared with the insulin-stimulated transport (Fig. 3).
Because the various experimental treatments also resulted in large differences in skeletal muscle cAMP (Fig. 5), it was possible to compare the changes in intramuscular cAMP with changes in plasma membrane GLUT-4 and 3-MG transport. When no insulin was present, the plasma membrane GLUT-4 (P < 0.05) and 3-MG transport were increased (P < 0.05) at the points when cAMP concentrations were also increased (Fig. 6A). Maximal effects on both GLUT-4 and 3-MG transport had already occurred with an ~25% increase in cAMP concentrations, since no further changes were observed thereafter (P > 0.05). In the presence of both insulin and epinephrine, there was a much wider range of cAMP concentrations (Fig. 6B). However, there was no obvious relationship between cAMP and plasma membrane GLUT-4 (Fig. 6B), whereas the insulin-stimulated 3-MG transport was lowered in relation to concurrent reductions in cAMP (P < 0.05; Fig. 6B).
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DISCUSSION |
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In the present studies we have shown that 1) epinephrine increased the GLUT-4 appearance in the plasma membrane, 2) similar increases in surface GLUT-4 could be provoked by insulin or epinephrine, 3) epinephrine increased basal glucose transport in all types of skeletal muscles, and 4) whereas plasma membrane GLUT-4 content remained elevated, insulin-stimulated glucose transport was greatly reduced by epinephrine. These results suggest that epinephrine reduced the glucose transport capacity of GLUT-4, but only when insulin was present.
Effects of epinephrine alone on 3-MG transport and GLUT-4. In the present studies epinephrine (25-150 nM) alone stimulated 3-MG transport in rat skeletal muscles. The maximal 3-MG transport increase occurred at a high physiological concentration of epinephrine (25 nM), with no further changes at the higher epinephrine concentrations (50 and 150 nM). Others have previously shown that epinephrine stimulated glucose transport in incubated rat skeletal muscles (38) and in perfused rat skeletal muscles (4, 43). In contrast, pharmacological concentrations of epinephrine (1 µM) (24) or high concentrations of isoproterenol (1 µM) (45) inhibit glucose transport in isolated muscles (24, 45). A similar dose-response effect of isoproterenol on glucose transport has also been observed in adipocytes [i.e., low isoproterenol concentrations (1-10 nM) increased glucose transport; high concentrations (1 µM) inhibited glucose transport (26, 34)]. In preliminary studies, high concentrations of epinephrine (>150 nM) caused high perfusion pressures in our preparation, resulting in edema, thereby limiting the epinephrine concentrations that can be used in perfused rat hindquarters.
It is very unlikely that the effects of epinephrine on glucose transport were mediated by GLUT-1. In Chinese hamster ovary (CHO) cells that express only GLUT-1, glucose transport was not altered by very high concentrations of DBcAMP (10 mM). In contrast, in CHO cells that express only GLUT-4, DBcAMP inhibited glucose transport (39). Moreover, GLUT-1 in muscle is found only on the plasma membrane (6, 20); hence glucose transport cannot be increased by translocating this transporter. Collectively, these studies suggest that the epinephrine effects on glucose transport are not due to GLUT-1 but are most likely mediated by the actions of epinephrine on GLUT-4. From our studies it appears that epinephrine induced the translocation of GLUT-4 from intracellular locations to the plasma membrane. This confirms an earlier study from our laboratory in which a bolus injection of epinephrine increased plasma membrane GLUT-4 and lowered intracellular membrane GLUT-4 in muscle (1). Several studies, using adipocytes, have attributed increases in glucose transport to GLUT-4 translocation by means of cAMP-dependent mechanisms. With low DBcAMP concentrations (10 µM), GLUT-4 was translocated and glucose transport was increased in adipocytes (28, 34). In the present studies the epinephrine-induced increase in cAMP was associated with an increase in plasma membrane GLUT-4 and glucose transport in muscle. Thus the most parsimonious explanation for our observations would seem to be that epinephrine by itself induces GLUT-4 translocation, possibly involving a cAMP-dependent mechanism, and that this increase in the plasma membrane GLUT-4 resulted in a greater 3-MG transport.Simultaneous effects of epinephrine and insulin on 3-MG transport
and GLUT-4.
Very different results occurred in our studies in the presence and in
the absence of insulin. The insulin-stimulated glucose transport was markedly inhibited by epinephrine in perfused muscles. This has also been observed in muscle in previous studies (4). In
studies with adipocytes (28) and L6 myoblasts (31), insulin-stimulated glucose transport was inhibited by high concentrations of the cAMP
derivative DBcAMP (1-2 mM) (28, 31), although low concentrations of DBcAMP (10 µM) did not inhibit insulin-stimulated glucose
transport in adipocytes (28). We also observed differences in responses among the muscles. In SOL the decrease occurred in a dose-dependent manner, whereas in RG and WG maximal inhibition was observed at the
lowest epinephrine concentration used (25 nM). However, the absolute
inhibition, as well as the relative inhibition (%), of 3-MG transport
was much greater in RG and SOL than in WG. The greater -adrenergic
responsiveness of oxidative muscles is presumably associated with the
greater number of
-adrenergic receptors in these muscles (23, 47,
48).
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ACKNOWLEDGEMENTS |
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These studies were supported by grants from the Natural Sciences and Engineering Research Council of Canada and the Canadian Diabetes Association in honor of George Goodwin.
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FOOTNOTES |
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Address reprint requests to A. Bonen.
Received 20 June 1997; accepted in final form 18 December 1997.
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