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invited review
Exercise regulation of glucose transport
in skeletal muscle
TATSUYA HAYASHI,1 JØRGEN F. P. WOJTASZEWSKI,2 AND LAURIE J. GOODYEAR1
Division, Joslin Diabetes Center, Department of Medicine, Brigham
and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02215;
and 2Copenhagen Muscle Research Centre, August Krogh Institute,
University of Copenhagen, DK-2100 Copenhagen, Denmark
1Research
Hayashi, Tatsuya, Jørgen F. P. Wojtaszewski, and Laurie J.
Goodyear. Exercise regulation of glucose transport in skeletal muscle.
Am. J. Physiol. 273 (Endocrinol. Metab. 36): E1039–E1051, 1997.—
Exercise increases the rate of glucose uptake into the contracting skeletal
muscles. This effect of exercise is similar to the action of insulin on
glucose uptake, and the mechanism through which both stimuli increase
skeletal muscle glucose uptake involves the translocation of GLUT-4
glucose transporters to the plasma membrane and transverse tubules.
Most studies suggest that exercise and insulin recruit distinct GLUT-4containing vesicles and/or mobilize different ‘‘pools’’ of GLUT-4 proteins
originating from unique intracellular locations. There are different
intracellular signaling pathways that lead to insulin- and exercisestimulated GLUT-4 translocation. Insulin utilizes a phosphatidylinositol
3-kinase-dependent mechanism, whereas the exercise signal may be
initiated by calcium release from the sarcoplasmic reticulum leading to
the activation of other signaling intermediaries, and there is also
evidence for autocrine- or paracrine-mediated activation of transport.
The period after exercise is characterized by increased sensitivity of
muscle glucose uptake to insulin, which can be substantially prolonged in
the face of carbohydrate deprivation. The ability of exercise to utilize
insulin-independent mechanisms to increase glucose uptake in skeletal
muscle has important clinical implications, especially for patients with
diseases that are associated with peripheral insulin resistance, such as
non-insulin-dependent diabetes mellitus.
muscle contraction; glucose transporters; GLUT-4; calcium; insulin
DURING PHYSICAL EXERCISE the increased requirement
for metabolic substrates in the working muscles is met
partially through the enhanced utilization of glucose.
To meet this increased need, there is a significant
elevation in the rate of glycogenolysis in the contracting muscles. In addition, exercise has an ‘‘insulin-like
effect’’ to increase the uptake of glucose from the
circulation into the working muscles. In the period
after exercise, muscle glucose uptake is more sensitive
to insulin, an effect that facilitates the resynthesis of
muscle glycogen stores. Both the acute and persistent
effects of exercise on glucose uptake and glycogen
metabolism have important implications for individuals with insulin resistance, because these changes can
effect the acute regulation of glucose homeostasis as
well as chronic metabolic control. Several excellent
reviews have described the effects of exercise on glucose
uptake in skeletal muscle (17, 50, 95, 103, 122). The
current review will discuss work from the last six to
seven years that has focused on elucidating the underlying molecular mechanisms for the changes in glucose
uptake that occur in skeletal muscle during and after a
single bout of physical exercise.
EFFECTS OF EXERCISE ON THE GLUCOSE
TRANSPORT SYSTEM
Under normal physiological conditions, glucose transport is the rate-limiting step in glucose utilization (69).
Glucose transport occurs primarily by facilitated diffusion, an energy-independent process that uses a carrier
protein for transport of a substrate across a membrane.
The glucose transporter carrier proteins in mammalian
tissues are a family of structurally related proteins that
are expressed in a tissue-specific manner (5). GLUT-4 is
the major isoform present in both human and rat
skeletal muscle, whereas the GLUT-1 and GLUT-5
isoforms are expressed at a much lower abundance (58,
62). The major mediators of glucose transport activity
0193-1849/97 $5.00 Copyright r 1997 the American Physiological Society
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in muscle are fiber contractions and insulin, although
numerous other factors including catecholamines, hypoxia, growth factors, and corticosteroids can alter glucose transport. Glucose transport in skeletal muscle
follows saturation kinetics, and most reports have
shown that exercise and insulin increase glucose transport through an increase in the maximal velocity of
transport (Vmax ) without an appreciable change in the
substrate concentration at which glucose transport is
half-maximal, or Km (43, 52, 86, 87). This increase in
transport Vmax may occur through an increase in the
rate that each carrier protein transports glucose (transporter turnover number), an increase in the number of
functional glucose transporter proteins present in the
plasma membrane, or both.
Glucose Transporter Translocation
In the early 1980s studies in rat adipose cells demonstrated that a major mechanism for the insulin-induced
increase in glucose transport was through stimulating
the movement of glucose transporter proteins from an
intracellular ‘‘microsomal’’ compartment to the plasma
membrane (19, 114). Despite its physiological importance, parallel studies were not initially performed in
skeletal muscle because the complex ultrastructure
and great abundance of contractile proteins made it
very difficult to prepare subcellular fractions from this
tissue. However, by the late 1980s, essentially two
different techniques for the preparation of intracellular
and plasma membranes had been developed for use in
skeletal muscle (48, 49, 64, 112). These methods, which
we will refer to as the Klip (64) and Hirshman-modified
Grimditch (48) techniques, have been the most commonly used preparations for the study of glucose transporter physiology in rat, mouse, and human skeletal
muscle. The membrane fractions derived from these
preparations, or modifications thereof, have been used
to measure total glucose transporter number by use of
the cytochalasin B binding assay, GLUT-1 and GLUT-4
proteins by immunoblotting, and the rate of glucose
transport into the isolated plasma membrane vesicles.
An inherent weakness associated with preparing subcellular fractions in skeletal muscle is the relatively low
recovery of plasma membranes (#15%). In addition,
although the preparations are devoid of sarcoplasmic
reticulum and mitochondrial membranes, there is often
some degree of cross contamination of plasma and
intracellular membranes. Despite these limitations,
the use of these fractionation methods over the past
several years has substantially advanced our fundamental understanding of the glucose transport system in
skeletal muscle.
To test the hypothesis that the translocation of
glucose transporters is a major mechanism by which
physical exercise increases glucose uptake, initial experiments studied skeletal muscles obtained from rats
that were exercised by running on a motorized rodent
treadmill. By use of either the Hirshman/Grimditch or
Klip fractionation technique, in all but one study (113)
exercise has consistently been reported to increase the
number of glucose transporters in the plasma mem-
brane fraction (Table 1) (23–25, 29, 36–38, 49, 102,
106). In addition, sciatic nerve stimulation, resulting in
contraction of hindlimb skeletal muscles in situ, also
increases plasma membrane glucose transporter number in the rat (9, 27, 31, 39). The exercise-induced
translocation of glucose transporters is due to an
increase in the plasma membrane content of the GLUT-4
isoform, because a single bout of exercise does not alter
the abundance of plasma membrane GLUT-1 (23, 36,
38) or GLUT-5 (66). Exercise-induced GLUT-4 translocation occurs in both red and white skeletal muscle
fibers (38) and also apparently occurs in response to
swim exercise in rats (16). In addition to subcellular
fractionation methods, sarcolemmal giant vesicles have
been prepared and used to study the effects of exercise
on GLUT-4 translocation in skeletal muscle (94). Although the use of these giant vesicles is limited because
of very low protein recoveries and a failure to respond
to insulin stimulation (94), this technique has recently
been used to demonstrate that both maximal (67) and
submaximal (68) bicycle exercise significantly increases sarcolemmal GLUT-4 protein in human vastus
lateralis muscle.
Similar to the effects of physical exercise, insulin also
causes GLUT-4 translocation in rat skeletal muscle (23,
38, 39, 48). Because blood flow is increased during
exercise, it could be hypothesized that the exerciseinduced recruitment of GLUT-4 to the plasma membrane is secondary to increased delivery of insulin to
the working muscles. However, when hindlimb skeletal
muscles are contracted in situ in the absence of insulin,
plasma membrane GLUT-4 is increased to a similar
degree to what occurs with exercise in vivo (9, 27, 31,
39). These findings demonstrate that contraction can
recruit GLUT-4 to the plasma membrane in rat skeletal
muscle independently of insulin, and they provide a
mechanism for earlier reports showing that insulin is
not required for muscle contraction to increase glucose
uptake in skeletal muscle (92, 100, 124).
The plasma membrane fractions that are derived
from both the Klip and Hirshman/Grimditch preparations are a mixture of both surface membranes and
transverse tubules, the membrane folds that extend
inward from the plasma membrane (78 and M. F.
Hirshman, E. S. Horton, and L. J. Goodyear, unpublished observations). By a modification of the Klip
procedure to separate transverse tubules from outwardfacing surface membranes (78), it has been estimated
that a significant percentage of the GLUT-4 that is
translocated to the plasma membrane fraction with
exercise associates with nonjunctional transverse tubules (102). The exercise-induced redistribution of
GLUT-4 to transverse tubules probably functions to
increase the overall rate of glucose transport into the
muscles and facilitate glucose transport deep into the
contracting muscle fibers (102).
Although numerous studies have used subcellular
fractionation methods to demonstrate that exercise and
insulin stimulate the redistribution of GLUT-4 to the
plasma membrane in skeletal muscle, more recently a
technique that measures cell surface GLUT-4 protein
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INVITED REVIEW
Table 1. Effects of exercise on the subcellular distribution of glucose transporters in normal rat skeletal muscle
Method/Assay
Exercise Effect
PM Transporters
Treatment*
Exercise 1 Insulin
PM Transporters
Exercise Effect
IM Transporters
Hirshman et al.
1988 (49)
Fractionation—H/G
CB binding
Treadmill run, 60 min
> 100%
Douen et al.
1989 (24)
Fractionation—Klip
CB binding
Treadmill run, 45 min
> 100%
&
Fushiki et al.
1989 (29)
Fractionation—H/G
and Klip
CB binding
Treadmill run, 2 hr
> 54% (H/G)
> 47 (Klip)
< 48% (H/G)
< 81% (Klip)
Sternlicht et al.
1989 (113)
Fractionation—H/G
CB binding
Treadmill run, 45 min
Insulin injection
&
No additive effect, but
no effect of exercise
alone
Goodyear et al.
1990 (39)
Fractionation—H/G
CB binding
Hindlimb perfusion
with contraction,
insulin
> 72%
No additive effect, but
no effect on glucose
uptake
Goodyear et al.
1990 (37)
Fractionation—H/G
CB binding
Treadmill run, 60 min > 80% 0 min post
Muscles obtained 0, 30, > 60% 30 min post
or 120 min postexer- & 120 min post
cise
Douen et al.
1990 (23)
Fractionation—Klip
CB binding, GLUT-4
blotting
Treadmill run, 45 min > 65% CB binding
Insulin hindlimb perfu- > 150% GLUT-4
sion
Douen et al.
1990 (25)
Fractionation—Klip
CB binding, GLUT-4
blotting
Treadmill run, 45 min
> 60% CB binding
> 150% GLUT-4
&
Goodyear et al.
1991 (36)
Fractionation—H/G
CB binding, GLUT-4
blotting
Treadmill run, 60 min
> 50% CB binding
> 45% GLUT-4
< 30% CB binding
< 25% GLUT-4
Goodyear et al.
1991 (38)
Fractionation—H/G
CB binding, GLUT-4
blotting
Treadmill run, 60 min CB binding:
Red & white gastrocne> 40% red, 100%
mius muscle studied
white
GLUT-4:
> 75% red, 79% white
Etgen et al.
1993 (27)
Fractionation—H/G
GLUT-4 blotting
Hindlimb perfusion
with contraction
> 67%
Brozinick et al.
1994 (9)
Fractionation—H/G
CB binding, GLUT-4
blotting
Hindlimb perfusion
with contraction,
insulin
> 96% CB binding
> 62% GLUT-4
No additive effect
& CB binding
& GLUT-4
Gao et al.
1994 (31)
Fractionation—H/G
GLUT-4 blotting
Insulin infusion followed by contraction
in situ
> 113%
Fully additive effect
< 25%
Lund et al.
1995 (75)
Bis-mannose photolabel with GLUT-4
Contraction, insulin of
soleus muscles in
vitro
> 397%
Partially additive
(84%)
Coderre et al.
1995 (16)
Fractionation—modi- Swimming, 30 min
fied Klip
GLUT-4 blotting
Sherman et al.
1996 (106)
Fractionation—H/G
GLUT-4 blotting
Treadmill run, 60 min
Roy and Marette Fractionation—modi- Treadmill run, 45 min
1996 (102)
fied Klip
GLUT-4 blotting
No additive effect using &
either assay
&
< 45% in novel fraction
> 40%
< 48%
> 95% PM
> 60% t tubules
< 40% in novel fraction
PM, plasma membrane; IM, intracellular membrane; H/G, Hirshman-modified Grimditch fractionation technique; CB, cytochalasin B; t
tubules, transverse tubules. * Insulin treatment is included only if the combination of exercise/contraction and insulin was studied.
using a membrane-impermeable bis-mannose photolabel has been developed (54). By use of this exofacial
labeling method, measurement of plasma membrane
GLUT-4 protein is not affected by contamination of
GLUT-4 originating from internal membranes, resulting in low basal levels of plasma membrane glucose
transporters and significantly greater multiples of increase in response to various stimuli. Indeed, when this
method was adapted to study rat soleus muscles incubated in vitro (75, 125), contraction increased plasma
membrane GLUT-4 protein by nearly fourfold (75).
Immunocytochemical analysis of skeletal muscle sec-
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INVITED REVIEW
tions by electron microscopy has also been used to
study the subcellular distribution of GLUT-4. Although
not studied individually, the combination of exercise
and insulin results in a substantial increase in GLUT-4
immunodetected in the plasma membranes (101). Taken
together, all of these studies provide overwhelming
evidence that a major mechanism for the exerciseinduced stimulation of glucose uptake in skeletal muscle
involves the recruitment of glucose transporters to the
plasma membrane. Furthermore, contraction in the
absence of insulin, as well as insulin alone, can independently result in the movement of glucose transporters
to the plasma membrane (Fig. 1).
The increase in muscle glucose transport with the
combination of a maximal contraction stimulus and a
maximal insulin stimulus is greater than the effect of
either contraction or insulin alone (32, 87, 123, 134).
This ‘‘additive’’ effect of contraction plus insulin on
glucose transport is consistent with the hypothesis that
the two stimuli can act independently. If the amount of
GLUT-4 in the plasma membrane is the limiting factor
for glucose transport, the combination of contraction
and insulin should result in a similarly additive effect
on the recruitment of GLUT-4 to the plasma membrane. However, there has been considerable discrepancy among studies that have examined this question
(Table 1) (9, 23, 31, 75). When treadmill exercise (23) or
contractions in situ (9) were combined with a maximal
insulin treatment, there was a partially additive effect
on muscle glucose uptake, but the increase in plasma
membrane glucose transporters was not greater than
the effect of exercise or insulin alone. These results,
which assessed glucose transporters in plasma membranes purified by fractionation, suggest that the additive effect of exercise and insulin on glucose uptake is
due to an increase in transporter turnover number. In
contrast to these findings is a study that also used
subcellular fractionation methods but reported that the
combination of insulin with contractions in situ has a
fully additive effect on increasing plasma membrane
GLUT-4 (31). Furthermore, with use of the exofacial
labeling method in rat soleus muscles, the combination
of contraction and insulin treatments resulted in an
almost completely additive increase in plasma membrane GLUT-4 protein (75). Thus the results of two
studies suggest that the increase in GLUT-4 at the
plasma membrane is the sole mechanism for the increase in glucose transport (31, 75), whereas the two
other studies raise the possibility that exercise increases glucose transporter turnover number (9, 23), a
process that is frequently referred to as ‘‘intrinsic
activity.’’
Fig. 1. GLUT-4 translocation in skeletal muscle. Muscle contractions and insulin cause translocation of GLUT-4
glucose transporter proteins to plasma membrane and transverse tubules (T-tubules). GLUT-1 and GLUT-5 are
present in plasma membrane. The subcellular origin of GLUT-4-containing vesicles is not clear, but exercise and
insulin appear to recruit distinct GLUT-4-containing vesicles and/or mobilize different ‘‘pools’’ of GLUT-4 proteins.
Insulin-stimulated GLUT-4 translocation involves insulin receptor substrate 1 (IRS-1) and phosphatidylinositol
(PI) 3-kinase and redistribution of Rab4. Contraction utilizes a PI 3-kinase- and mitogen-activated protein kinase
(MAPK)-independent mechanism and does not result in redistribution of Rab4. Contraction signal is probably
initiated by release of calcium from sarcoplasmic reticulum and may involve an autocrine/paracrine mechanism
(e.g., nitric oxide, adenosine, bradykinin), protein kinase C (not shown), or a combination of these and other
currently unknown factors. NO, nitric oxide; JNK, c-Jun NH2-terminal kinase.
INVITED REVIEW
Glucose Transporter Turnover Number
In most early studies of adipose cells and skeletal
muscle, the incremental increase in the rate of insulinor exercise-stimulated glucose transport was greater
than the increased recruitment of glucose transporters
to the cell surface, suggesting an increase in transporter turnover number. To measure transporter turnover number in skeletal muscle, glucose transport into
isolated plasma membrane vesicles is assayed using
the same plasma membrane preparation that is used to
measure total glucose transporter number by the Dglucose-inhibitable cytochalasin B binding assay (38,
60). The transporter turnover number is calculated by
dividing the glucose transport Vmax by the total glucose
transporter number (R0 ), which is determined by
Scatchard analysis of cytochalasin B binding data in
the absence or presence of glucose. By use of these
methods, exercise was shown to increase glucose transport Vmax by fourfold and R0 by twofold, resulting in a
doubling of the transporter turnover number and suggesting that the mechanism for the exercise-induced
increase in skeletal muscle glucose uptake involves
both the translocation of glucose transporters to the
plasma membrane and an increase in the average
intrinsic activity of the transporters that are present in
the plasma membrane (38, 60). One limitation of this
method is that it does not discriminate the activity of
the individual glucose transporter isoforms, and thus a
change in activity could reflect the recruitment of a
more active transporter isoform to the plasma membrane. In fact, studies using Xenopus laevis oocytes
suggest that GLUT-4 has a higher intrinsic activity
than GLUT-1 (88) and, as discussed above, only GLUT-4
is recruited to the plasma membrane in response to
exercise (23, 36, 38). When transporter translocation is
assessed using the GLUT-4-specific exofacial labeling
method, the contraction-stimulated increases in the
rate of glucose transport into the isolated soleus muscles
and GLUT-4 recruitment to the plasma membrane
were nearly identical (75). Thus, although there may be
some conditions that directly modify glucose transporter activity (111), it is unlikely that exercise increases the intrinsic activity of the individual glucose
transporter isoforms. Instead, exercise probably increases the average turnover number of all transporters in the plasma membrane by recruiting the more
active GLUT-4.
Separate ‘‘Pools’’ of Glucose Transporters for Exercise
and Insulin?
If the combination of exercise and insulin has additive effects on glucose transport and GLUT-4 recruitment to the plasma membrane, then at some level there
must be different mechanisms leading to the stimulation of muscle glucose transport. Data from several
studies have suggested that this could result from two
distinct intracellular locations or pools of glucose transporters, one that responds to exercise and one that
responds to insulin (23–25). In these reports, insulin,
but not exercise, was shown to decrease glucose trans-
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porters from an intracellular microsomal membrane
fraction (Table 1). Interestingly, the differential effects
of exercise and insulin to decrease glucose transporters
in the intracellular membrane fraction have only been
consistently demonstrated when the Klip fractionation
procedure was used, suggesting that the Klip and
Hirshman/Grimditch methods isolate different populations of intracellular membranes. Recently, modification of the Klip procedure has resulted in the isolation
of a novel intracellular membrane fraction that is
sensitive to exercise (16, 102), giving further support to
the hypothesis that there are separate pools of glucose
transporters in skeletal muscle. Surprisingly, although
there are different sedimentation coefficients for the
insulin- and exercise-sensitive fractions, there appears
to be very little difference in the major protein composition of these fractions (16).
Regulation of GLUT-4 Vesicular Translocation
The majority of intracellular GLUT-4 is located in
small tubulo-vesicular organelles (48, 101), and it is
still not completely clear whether these vesicles are
unique intracellular compartments or ubiquitously expressed organelles that are enriched in GLUT-4. As has
recently been reviewed in detail (111), most studies in
adipose cells suggest that there is a low rate of continuous recycling of GLUT-4 in the basal state and that
insulin acts primarily through increasing transporter
exocytosis. The molecular mechanism by which exercise stimulates the movement of these GLUT-4-containing vesicles to the cell surface in skeletal muscle is not
known. Proteins that have been identified as components of GLUT-4-containing vesicles in skeletal muscle
include the vesicle-associated membrane protein-2
[VAMP-2; also called synaptobrevin 2 (67, 121)], cellubrevin [also called VAMP-3 (121)], gp160 (16, 80), and
Rab4 (106). Both gp160 (16) and VAMP-2 (67) have
been shown to translocate in response to physical
exercise in skeletal muscle, similar to the effects of
insulin.
In contrast to the similar effects of exercise and
insulin on gp160 and VAMP-2 distribution, there are
differential effects of exercise and insulin on the redistribution of Rab-4 (106). Rab proteins are guanosine
triphosphate (GTP)-binding proteins that are thought
to be involved in all vesicular activity (formation,
targeting, fusion) and may act as molecular switches,
catalyzing membrane trafficking events by conversion
from an inactive guanosine diphosphate-bound form to
an active GTP-bound form (109, 118). Studies in adipose cells suggest that the Rab4 isoform is involved in
insulin-stimulated GLUT-4 translocation (18, 108). By
use of the Hirshman/Grimditch fractionation technique
in skeletal muscle, both insulin and exercise have been
shown to decrease GLUT-4 in the microsomal membranes, but only insulin caused a redistribution of Rab4
from this fraction (106). Consistent with these findings
is work showing that insulin and exercise both cause an
increase in the plasma membrane content of small
GTP-binding proteins (as assessed by [32P]GTP-binding
overlay assays), whereas only insulin treatment re-
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INVITED REVIEW
sulted in a concomitant decrease in these proteins in
the intracellular microsomal fraction (27). Although
these experiments using nonspecific GTP-binding proteins and Rab4 as markers do not necessarily contradict the hypothesis that insulin- and exercise-stimulated transporters originate from different locations in
the muscle fibers, the findings do suggest that there
may be distinct GLUT-4-containing vesicles, some that
are sensitive to insulin and some that are sensitive to
exercise. Thus there could be a common subcellular
location of transporters with different molecular
‘‘switches’’ for mobilization. Future studies will be
necessary to determine the exact location of exerciseand insulin-stimulated GLUT-4 vesicles and the vesicular machinery that regulates the redistribution of these
organelles in skeletal muscle.
SIGNALING MECHANISMS FOR EXERCISE-STIMULATED
GLUCOSE TRANSPORT
Whereas considerable progress has been made in understanding the role of glucose transporter proteins in
the stimulation of glucose transport with exercise, much
less is known about the intracellular signaling mechanisms that lead to exercise-stimulated GLUT-4 translocation. However, over the past several years there have
been many advances in elucidating the signaling components involved in insulin-stimulated GLUT-4 translocation. Because exercise and insulin both increase glucose uptake through the translocation of GLUT-4,
several studies have determined whether these two
stimuli share the same signaling intermediaries.
Phosphatidylinositol 3-Kinase
Numerous studies in various cell types have demonstrated that the activation of phosphatidylinositol 3kinase (PI 3-kinase) is necessary for the stimulation of
GLUT-4 translocation (see reviews in 13, 14). In skeletal muscle, insulin stimulation results in the rapid
phosphorylation of the insulin receptor and insulin
receptor substrate 1 (IRS-1) on tyrosine residues and
activation of PI 3-kinase (28, 34). Inhibition of PI
3-kinase by pharmacological blockade by wortmannin
has shown that PI 3-kinase is an essential molecule for
insulin-stimulated GLUT-4 translocation (75) and glucose transport (73–75, 127, 129) in skeletal muscle. In
contrast, these initial signaling events in insulin action
that lead to GLUT-4 translocation do not appear to be
involved in the mechanism for exercise-stimulated
glucose transport. Exercise has no effect on autophosphorylation of isolated insulin receptors (99), and contraction of hindlimb muscles by electrical stimulation
of sciatic nerves has no effect on tyrosine phosphorylation of the insulin receptor and IRS-1 or PI 3-kinase
activity (34, 127). Furthermore, wortmannin does not
inhibit glucose transport in isolated rat muscle incubated and contracted in vitro (73, 75, 129). In contrast
to these findings, one study has shown that wortmannin can partially inhibit contraction-stimulated glucose
transport in perfused rat hindlimb muscles without
confounding effects on contractility or oxygen uptake
(127). However, this effect of wortmannin might be
independent of effects on PI 3-kinase (127). Thus the
majority of studies suggest that, although exercise and
insulin both recruit GLUT-4 to the plasma membrane
and activate glucose transport, there are distinct signaling mechanisms that lead to the translocation of glucose transporters in skeletal muscle.
Calcium and Protein Kinase C
Muscle contraction is initiated by depolarization of
the plasma membrane, triggering the release of calcium from the sarcoplasmic reticulum. The spike in
intracellular calcium leads to the interaction of actin
and myosin filaments, resulting in the development of
tension in the muscle fibers. Of these events, the
increase in cytoplasmic calcium concentrations has
long been considered a critical mediator or initiator of
contraction-stimulated glucose transport (50), and this
topic has recently been reviewed in detail (51). The
calcium hypothesis is supported by various lines of
evidence, including an early study in amphibian muscle
showing that the incremental increase in contractionstimulated transport correlates with the frequency of
contraction, not the amount of work or tension developed (52). A role for membrane depolarization in contraction-stimulated glucose transport was also ruled out by
an early study showing that caffeine, an agent that
causes contraction by increasing calcium release from
the sarcoplasmic reticulum in the absence of membrane depolarization, increases glucose transport in
isolated amphibian muscle (53). Several studies have
shown that rates of glucose transport are increased in
mammalian muscle when cytoplasmic calcium concentrations are raised using various agents (45, 50, 130),
and dantrolene, which prevents the release of calcium
from sarcoplasmic reticulum, blocks glucose transport
in skeletal muscle (89, 130). All of these studies provide
indirect evidence that exercise utilizes a calciumsensitive glucose transport system. However, it should
be noted that, although calcium can activate glucose
transport in skeletal muscle, an increase in intracellular calcium does not share all the characteristics of
exercise. For example, calcium-induced glucose transport actually inhibits insulin-induced glucose transport
(26, 72), a response that clearly contrasts with the
effects of exercise. If calcium is involved in regulating
exercise-stimulated glucose transport, then calcium
ions probably do not directly activate the glucose
transport system. This is because cytoplasmic calcium
concentrations are elevated for only a fraction of a
second after each muscle contraction, whereas the
increase in muscle glucose transport can remain elevated for a considerable period of time after the contractile activity ceases. Instead, the rise in cytosolic calcium
may initiate or facilitate the activation of intracellular
signaling molecules or cascades of signaling proteins
that lead to both the immediate and prolonged effects of
exercise on muscle glucose transport.
Protein kinase C (PKC) is an example of a calciumdependent signaling intermediary that may be activated by muscle contraction (15, 96). Downregulation of
INVITED REVIEW
PKC by long-term phorbol ester treatment (15) and
inhibition of PKC using polymyxin B (47, 131) have
both been associated with decreases in contractionstimulated glucose transport. However, caution must
be taken in interpreting these data, because polymyxin
B is not a specific inhibitor of PKC, and both of these
treatments can result in decreased contractility of the
muscle fibers. Furthermore, early studies that measured PKC activity in muscle used the nonspecific
kinase substrate histone IIIS, and it is now known that
contraction can increase the activity of numerous kinases in skeletal muscle (1, 85). If PKC is involved in
regulating contraction-stimulated glucose transport,
then it will be important to determine which of the 12
different PKC isoforms that have been identified in
mammalian cells are responsible. PKC isoforms have
been classified into three subfamilies on the basis of
amino acid similarity and mode of activation: conventional PKCs (cPKC), novel PKCs (nPKC), and atypical
PKCs (aPKC). Skeletal muscles express the a, bI, and
bII isoforms (128 and D. J. Sherwood and L. J. Goodyear, unpublished observations), members of the cPKC
subfamily that are calcium dependent and sensitive to
phorbol ester stimulation. Because phorbol esters can
modestly stimulate glucose transport in skeletal muscle
(45, 56, 110), by analogy it is possible to deduce that if
these specific isoforms are stimulated by muscle contraction, they may be involved in the regulation of contraction-stimulated glucose transport. Interestingly, skeletal muscle also expresses very high levels of the u
isoform (128) and lower levels of the e, h, d, and z PKCs
(55, 128 and D. J. Sherwood and L. J. Goodyear, unpublished observations). These proteins belong to the nPKC
or aPKC subfamilies, isoforms that do not require
calcium for activation. If exercise stimulates these PKC
isoforms, it will be interesting to determine whether
they are involved in regulating glucose transport or
other biological effects of contraction in skeletal muscle.
Autocrine/Paracrine Mechanisms
Studies in cultured skeletal and cardiac muscle cells
have suggested that mechanical stretch can activate
intracellular signaling pathways by releasing growth
factors, which in turn stimulate cell surface receptors
and subsequently second messenger systems (104, 117).
In adult skeletal muscle, there is also evidence that
contracting skeletal muscle can evoke an autocrine
and/or paracrine response. This type of mechanism
may function to help activate cell-signaling molecules
such as PKC and subsequently lead to the increase in
glucose transport. Nitric oxide is an example of a
molecule that may act on skeletal muscle through an
autocrine or paracrine mechanism, and recent evidence
suggests that nitric oxide may be involved in regulating
contraction-stimulated glucose transport. Nitric oxide
is released from skeletal muscle contracted in vitro,
and inhibition of nitric oxide synthase has been demonstrated to decrease both basal (3) and contractionstimulated (4) rates of muscle glucose transport, an
effect that may be regulated by a guanosine 38,58-cyclic
monophosphate-mediated mechanism (2, 132). Interest-
E1045
ingly, consistent with the concept that exercise and
insulin act through distinct signaling mechanisms,
there was no effect of nitric oxide synthase inhibition on
insulin-stimulated glucose transport in skeletal muscle
(4). Another molecule that may be involved with contraction-stimulated glucose transport is kallikrein, which
catalyzes the production of bradykinin and is a potential stimulator of nitric oxide synthase. Kallikrein is
predominantly expressed in slow-twitch red muscles,
the fiber type that expresses greater amounts of GLUT-4
(81). Adenosine has also been shown to be secreted from
contracting muscle fibers (105), and the adenosine
receptor has been suggested to mediate the signaling
mechanism through which contraction results in the
synergistic stimulation of insulin-stimulated glucose
transport (119).
Other Putative Mechanisms
Several other intracellular signaling proteins have
been shown to be activated in response to physical
exercise; however, to date there is no evidence to
suggest that these molecules regulate contractionstimulated glucose transport. For example, exercise
activates the mitogen-activated protein (MAP) kinase
signaling cascade in both rat (33) and human (1)
skeletal muscle, but we have recently demonstrated
that inhibition of MAP kinase signaling by use of
pharmacological blockade (PD-98059) has no effect on
contraction-stimulated glucose transport in vitro (Hayashi and Goodyear, unpublished observations) or in the
perfused hindlimb (J. F. P. Wojtaszewski, A. B. Jacobsen, and E. A. Richter, unpublished observations). The
c-Jun NH2-terminal kinase (JNK) and p38 kinase
signaling cascades are also stimulated by physical
exercise in skeletal muscle (33). It is not known whether
these signaling cascades mediate the effects of contraction on carbohydrate metabolism, although one recent
report has suggested that JNK signaling is involved in
the regulation of insulin-stimulated glycogen synthesis
in skeletal muscle (84). Because these signaling cascades have been suggested to regulate gene transcription in other cell types, activation of these pathways by
acute exercise may function to regulate more chronic
adaptations to repeated bouts of exercise.
The glycogenolytic process may also play a role in the
regulation of exercise-induced GLUT-4 translocation in
skeletal muscle. Although there is still no direct evidence, it has long been hypothesized that transporter
molecules are associated with glycogen particles in the
muscle and that the contraction-stimulated hydrolysis
of glycogen releases GLUT-4, leading to translocation of
these transporters to the cell surface. Future studies
will be needed to directly test this hypothesis, and work
in other areas is needed to precisely define the role of
the other putative mechanisms that have been discussed in this review. With continued focus in this area,
along with the development of novel methodologies, we
should soon have a clearer understanding of the molecular basis for exercise-induced increases in muscle glucose uptake.
E1046
INVITED REVIEW
MECHANISMS FOR POSTEXERCISE INCREASES
IN MUSCLE INSULIN SENSITIVITY
Increased insulin sensitivity of skeletal muscle glucose uptake is usually observed after a single bout of
exercise. This was first shown in perfused rat muscles
(57, 97) and has since been verified in numerous human
studies (6, 21, 82, 99). By use of one-legged exercise
models, it has become clear that the exercise-induced
increase in insulin sensitivity is a local phenomenon
restricted to the exercised muscles (98, 99). In addition
to the glucose transport step (12, 97, 98, 123), prior
exercise potentiates insulin-stimulated glycogen synthesis (71, 97, 98) and amino acid transport (133). Carbohydrate deprivation in the postexercise period prolongs
the increased insulin sensitivity in rat muscle (12) and,
in fact, no reversal of the increased insulin sensitivity is
observed in incubated muscles when the nonmetabolizable 2-deoxyglucose is substituted for D-glucose (40).
Thus the rate that glucose is stored or metabolized in
the postexercise period may be involved in the reversal
of the increased insulin sensitivity of muscle glucose
uptake and may partially explain the different durations of the increased insulin sensitivity reported (20,
82, 91, 97).
Several studies have determined whether enhanced
insulin binding or insulin signaling are mechanisms for
the increase in muscle insulin sensitivity after exercise.
However, there is no difference in insulin clearance
rates between rested and exercised legs 4 h after
one-legged exercise in humans (99), and the majority of
studies show that prior exercise does not change insulin binding to its receptor (7, 115, 133). Prior exercise
does not increase insulin-stimulated receptor tyrosine
kinase activity in skeletal muscles obtained from rats
(115) or humans (126) and, in fact, prior contraction of
rat hindlimb skeletal muscles has been shown to cause
a paradoxical decrease in insulin-stimulated tyrosine
phosphorylation of the insulin receptor and IRS-1, and
receptor- and IRS-1-associated PI 3-kinase activities
(34). Consistent with these findings are recent studies
showing that insulin’s ability to activate IRS-1-associated PI 3-kinase activity in vivo is diminished in
previously exercised humans (126). This mismatch
between the signaling events and the end point of
cellular activation (glucose uptake) suggests that IRS1-associated PI 3-kinase activity is not the sole mediator of insulin-stimulated glucose transport in skeletal
muscle. Furthermore, these findings provide additional
support to the hypothesis that exercise and insulin act
through distinct signaling mechanisms.
Clues leading to the mechanism of increased insulin
sensitivity may come from studies in which the postexercise period is not characterized by increased insulin
sensitivity. In contrast to exercise in vivo (98) or
contraction of hindlimb muscles during perfusion (100),
when intact muscles are isolated, washed, and then
contracted in vitro, there is no increase in insulin
sensitivity after contractions (11). This work and a
subsequent report have suggested that a serum factor,
probably a protein, is required for the effects of contrac-
tion to enhance insulin sensitivity (30). Other work has
indicated that adenosine receptors may mediate the
ability of muscle contraction to increase insulinstimulated glucose uptake (119), and another hypothesis, based on the finding that prior exercise can also
increase hypoxia-stimulated glucose transport, suggests that the glucose transport system is simply left in
a more easily recruitable state in the period after
glycogen-depleting exercise (11). Taken together, these
studies suggest that there may be no single factor that
regulates the enhanced muscle insulin sensitivity for
glucose uptake in the postexercise state. Instead, this
physiological phenomenon may be regulated by a combination of humoral factors, autocrine/paracrine mechanisms, and muscle glycogen concentrations.
EFFECTS OF EXERCISE ON GLUCOSE TRANSPORT
IN THE INSULIN-RESISTANT STATE
Exercise has long been advocated as beneficial for
patients with non-insulin-dependent diabetes mellitus
(NIDDM), partially because, even in the face of insulin
resistance, physical work can stimulate muscle glucose
uptake. This observation is consistent with the thesis
that exercise and insulin stimulate muscle glucose
transport by distinct mechanisms. Thus, it is not
surprising that a variety of animal models of insulin
resistance have been studied in an attempt to elucidate
the mechanisms for exercise- and insulin-stimulated
glucose transport.
The obese Zucker rat has severe defects in insulinstimulated glucose uptake (107) and GLUT-4 translocation (61) despite normal levels of total muscle GLUT-4
protein (107). In contrast, these animals have normal
increases in contraction-stimulated glucose uptake (8)
and GLUT-4 translocation (10, 59). Similarly, shortterm immobilization (120) and high-fat feeding (70),
two animal models that result in insulin resistance
with preserved muscle GLUT-4 protein concentrations,
also have normal rates of exercise-stimulated glucose
transport. However, longer periods of immobilization
(22, 93) and high-fat feeding (41) that decrease total
GLUT-4 protein in the muscle result in significant decreases in exercise-induced muscle glucose transport.
Impaired exercise-stimulated glucose transport is also
present when severe insulin resistance of muscle glucose transport and decreased muscle GLUT-4 mRNA
and protein levels are caused by a short period of
denervation (46, 116), treatment with streptozotocin
(63, 87, 124), or severe eccentric contractions (65).
These animal studies suggest that exercise-stimulated
glucose transport is impaired only under conditions in
which total muscle GLUT-4 protein is markedly decreased.
This is good news for patients with insulin-resistant
conditions such as obesity and NIDDM, because these
individuals generally have normal muscle GLUT-4
protein levels (42, 90). Indeed, in physiological models
of insulin resistance and in patients with NIDDM in
whom there is normal muscle GLUT-4 protein, the
ability of exercise to increase glucose disposal is preserved. Obese NIDDM patients have a normal increase
INVITED REVIEW
in peripheral glucose utilization during moderate exercise (83), and recently, by application of the arteriovenous balance technique, the exercise-induced increase
in leg glucose uptake was even higher in the nonobese
NIDDM compared with the control subjects (79). The
latter finding is probably caused by a greater mass
action of glucose because of hyperglycemia, i.e., the leg
glucose clearance rate in the exercise period was comparable in the nonobese NIDDM and control subjects. In
both obese and nonobese NIDDM patients, the exerciseinduced increase in muscle glucose uptake, coupled
with an impaired or delayed enhancement of hepatic
glucose production, can cause a decrease in plasma
glucose concentration (79, 83). The exercise-stimulated
increase in glucose uptake in patients with NIDDM is
probably a function of normal GLUT-4 translocation,
although this question must still be addressed experimentally. On the basis of data from human subjects and
the animal data discussed in previous sections, we can
now hypothesize that insulin-resistant human patients
can increase rates of muscle glucose uptake with exercise, because the muscle is able to bypass the previously
described defects in the insulin-signaling molecules
(35) and effectively activate the exercise-specific signaling mechanisms.
SUMMARY AND FUTURE DIRECTIONS
Over the past several years considerable progress
has been made in understanding the molecular basis
for the clinically important effects of physical exercise
on glucose uptake in skeletal muscle. We now know
that GLUT-4 plays a major role in regulating glucose
transport in muscle during exercise, and although the
exercise-induced signaling mechanism that leads to
GLUT-4 translocation has not been elucidated, we are
beginning to gain an understanding of this phenomenon. It is clear that exercise and insulin utilize distinct
signaling pathways that lead to the activation of glucose transport in skeletal muscle, perhaps explaining
why patients with insulin resistance can normally
activate muscle glucose transport with exercise but not
with insulin. Complete elucidation of the molecules
involved in signaling the exercise-induced activation of
glucose transport will be important, and these proteins
are potential sites for future pharmacological intervention. As we learn more about the signaling intermediaries that regulate the effects of exercise on glucose
transport, it will be critical to determine how these
molecules adapt with chronic physical training. Because it is now known that long-term regular physical
exercise can significantly reduce the risk of developing
NIDDM in most populations (44, 76, 77), these studies
should ultimately help us define the molecular basis for
these important adaptations to skeletal muscle.
This work was supported by National Institutes of Arthritis and
Musculoskeletal and Skin Diseases Grant AR-42238, a grant from
the Juvenile Diabetes Foundation International (both to L. J. Goodyear), and Grant 504–14 from the Danish National Research Foundation (to J. F. P. Wojtaszewski). T. Hayashi was supported by a
fellowship grant from the Manpei Suzuki Diabetes Foundation.
Address for reprint requests: L. J. Goodyear, Joslin Diabetes
Center, Boston, MA 02215.
E1047
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