Exercise Effects On Muscle Insulin Signaling and Action 2002 PDF

J Appl Physiol 93: 765772, 2002;
10.1152/japplphysiol.00267.2002.
highlighted topics
Exercise Effects on Muscle Insulin Signaling and Action
Exercise and insulin signaling: a historical perspective
S,1,2 ANTONIO ZORZANO,2 AND NEIL B. RUDERMAN1
EVA TOMA
1
Diabetes Unit, Section of Endocrinology, Boston Medical Center and Department
of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118;
and 2Department de Bioqumica i Biologia Molecular, Facultat de Biologia,
Universitat de Barcelona, 08028 Barcelona, Spain
Tomas, Eva, Antonio Zorzano, Neil B. Ruderman. Exercise and
insulin signaling: a historical perspective. J Appl Physiol 93: 765772, 2002;
10.1152/japplphysiol.00267.2002.Over the past 30 years, a considerable body of evidence has revealed that a prior bout of exercise can
increase the ability of insulin to stimulate glucose transport and glycogen synthesis in skeletal muscle. Apart from its clinical implications, this
work has led to a considerable effort to determine at a molecular level
how exercise causes this effect and, in particular, whether it does so by
enhancing specific events in the insulin-signaling cascade. The objective
of this review is to discuss from a historical perspective how our current
thinking in this area has evolved and the people responsible for it. Areas
to be discussed include the effect or lack of effect of prior exercise on the
insulin-signaling pathway, effects of exercise on the regulation by insulin
of the GLUT-4 glucose transporter in muscle, and the emerging role of
AMP-activated protein kinase as a mediator of exercise-induced signaling events. In addition, we will discuss briefly some of the avenues that
research in this area is likely to follow.
diabetes; glucose transport; 5-aminoimidazole-4-carboxamide ribofuranoside; AMP-activated protein kinase; skeletal muscle
(9) in 1887 reported that when a

horse chews on hay the concentration of glucose in the
blood draining its masseter muscle substantially decreases. This remarkable observation was the first
demonstration that glucose uptake by muscle is enhanced during exercise. In 1924, Sir Henry Dale in
England (6) and Carl and Gerti Cori in the United
States (11) demonstrated with their colleagues that
insulin also increases glucose uptake by muscle. This
review will focus on the interaction between insulin
and exercise in regulating glucose uptake and in particular will focus on the question of whether a prior
bout of exercise enhances the ability of insulin to stimulate glucose utilization by an effect on insulin signaling. For additional discussions of aspects of this subject
CHAUVEAU AND KAUFMAN
Address for reprint requests and other correspondence: N. B.

Ruderman, Diabetes Unit, Section of Endocrinology, Boston Medical Center and Dept. of Medicine, Boston Univ. School of Medicine, 650 Albany St., X-825, Boston, MA 02118 (E-mail:
nruderman@medicine.bu.edu).
http://www.jap.org
and of the signaling changes induced in muscle by

exercise per se, the reader is referred to a recent paper
by Richter et al. (46) and to an earlier review in this
series by Goodyear and Sakamoto (19).
ORIGIN OF THE NOTION THAT A PRIOR BOUT
OF EXERCISE ACUTELY ENHANCES
INSULIN ACTION ON MUSCLE
The first clue that exercise might enhance the ability

of insulin to stimulate muscle glucose utilization was
probably provided by Per Bjorntorp and his co-workers
in Gothenberg, Sweden in the early 1970s. In 1972 (3),
they reported that glucose tolerance was better and
plasma insulin levels lower in middle-aged Swedish
men who regularly participated in competitive sports
than in age- and weight-matched control men. The
same investigators also reported that 6 wk of physical
training lowered plasma insulin levels (although it did
not affect glucose tolerance) in a group of hyperinsulinemic, obese women (2, 4). Collectively, these results
led to the suggestion that regular exercise can increase
8750-7587/02 $5.00 Copyright 2002 the American Physiological Society
765
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HISTORICAL PERSPECTIVES
whole body and presumably muscle insulin sensitivity,

a notion subsequently confirmed in rats by Carl Mondon, Constantine Dolkas, and Gerald Reaven at Stanford (37).
Bjorntorps studies did not address the question of
whether the increase in insulin sensitivity associated
with physical activity is an acute or a chronic effect of
exercise. The fact that adipose tissue mass, fat cell size,
and plasma lipids (cholesterol and triglycerides) were
lower in the athletes whom they studied than in the
control men suggested the latter (3). On the other
hand, their observation that acute decreases in plasma
insulin could persist for several days after each individual exercise bout suggested the former (4). This
question aside, Bjorntorps research encouraged several groups to examine the effect of several months of
regular exercise on glucose tolerance in patients with
Type 2 diabetes, a disorder associated with insulin resistance. In the first of these studies, reported in 1979,
Bengt Saltin and co-workers in Sweden (49) and Neil
Ruderman and his colleagues at the Joslin research Laboratory in Boston (48) found modest improvements in
glucose tolerance in patients with chemical diabetes (impaired glucose tolerance) and diet-controlled Type 2 diabetes, respectively. On the other hand, the relative transience of the improvement (it had disappeared by 8 days
after the last exercise bout) found by the Ruderman
group led them to question whether it was the result of a
long-term effect of training, such as improved fitness.
This and their subsequent finding that hemoglobin A1C
levels can be markedly diminished by regular exercise in
similar patients with Type 2 diabetes (51) led them to
assess the effect of a single bout of exercise on insulin
action in skeletal muscle.
In studies that they carried out at Boston University,
Erik Richter and co-workers (47) used the isolated
perfused rat hindquarter preparation to demonstrate
that the ability of a physiological concentration of insulin (75 U/ml) to stimulate glucose uptake and glycogen synthesis in muscle is enhanced for several
hours after a 45-min treadmill run (Table 1). They
showed that this effect is restricted to muscles that had
performed work, as judged by glycogen depletion (47),
and that it was reproduced when hindquarter muscle
was made to contract by electrical stimulation of the
sciatic nerve. Antonio Zorzano et al. (62), working in
the same laboratory, later showed that prior exercise
enhances the ability of insulin to stimulate -aminoisobutyrate uptake by muscle, indicating that it also
acts on the Na-dependent A system for amino acid
transport. In 1990, Greg Cartee et al. (15), in the
laboratory of John Holloszy at Washington University
in St. Louis, reported that the period of increased
insulin sensitivity postexercise could be greatly prolonged if the rats were fasted or fed a low-carbohydrate
diet, a finding that they attributed to these nutritional
manipulations slowing the repletion of muscle glycogen stores. That prior exercise enhances insulin-stimulated glucose utilization in human muscle was first
reported in 1987 by John Devlin and Edward Horton at
the University of Vermont (13).
J Appl Physiol VOL
Table 1. Glucose utilization by the isolated perfused

rat hindquarter after treadmill running:
effect of insulin
Glucose Uptake, mol g1 h1
Insulin, U/ml
Control
Postexercise
0
10
30
75
500
20,000
40,000
1.8 0.2
2.2 0.3
1.9 0.2
3.2 0.2
6.3 0.1
10.2 0.9
10.6 0.2
4
8
4
12
3
8
3
1.9 0.4
2.8 0.2
2.7 0.2*
6.1 0.3*
9.4 1.1*
12.6 0.5*
12.1 0.2*
5
8
4
13
3
8
2
Values are means SE; n no. of observations. Hindquarters

were placed in the perfusion system 20 min after the cessation of a
30-min treadmill run or an equivalent period of rest. After 12 min of
equilibration, glucose utilization was measured over the next 45 min.
Control rats were not exercised. Insulin at the indicated concentrations was added to the initial cell free perfusate. Between 10 and 20%
of the insulin was degraded during the perfusion. * P 0.05, compared with control values. [Adapted from Ref. 47.]
Armed, in part, with the initial data from Richters

rodent studies, Stephen Schneider and co-workers at
the New Jersey College of Medicine and Boston University School of Medicine (50) carried out studies
suggesting that the decrease in hemoglobin A1C in
patients with Type 2 diabetes caused by physical training is due to the cumulative effect of the individual
exercise bouts rather than improved fitness. More specifically, in patients who experienced decreases of hemoglobin A1C in excess of 1% after several months of
physical training, Schneider et al. showed that glucose
tolerance was substantially better at 12 and 17 h than
at 72 h after the last bout of exercise. Concurrent
studies in nondiabetic athletes by Heath et al. in Holloszys laboratory (23) and by Burstein and Posner and
colleagues at McGill (7), demonstrating that the high
insulin sensitivity of trained individuals diminishes
rapidly (days) when these individuals cease exercising,
strongly supported this conclusion.
In summary, these early reports established beyond
question that a single bout of exercise enhances the
sensitivity and responsiveness of skeletal muscle to
insulin in both humans and experimental animals.
They suggested that both glucose and amino acid
transport are affected and that the effect of exercise is
mediated in great measure by local rather than systemic factors. They also suggested that much of the
apparent benefit of physical training on glycemic control and insulin sensitivity in patients with Type 2
diabetes is attributable to a residual effect of the last
bout of exercise. As will be discussed later, however,
cumulative effects of regular exercise in these patients
almost certainly also play a major role.
EFFORTS TO EXPLAIN AT A MOLECULAR LEVEL HOW
PRIOR EXERCISE ENHANCES INSULIN-STIMULATED
GLUCOSE TRANSPORT IN MUSCLE
Insulin signaling. The demonstration that prior exercise enhances certain actions of insulin in skeletal
muscle (47) took place at the same time that the early
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steps in the insulin-signaling cascade were being elucidated (32). For this reason, repeated efforts were
made over the next 15 years to determine whether
prior exercise alters the ability of insulin to stimulate
one or more signaling events (see Fig. 1). Initial studies
by Arend Bonen and co-workers in Canada (5) and by
Zorzano et al. (62) established that prior exercise does
not increase insulin binding to its receptor in rat skeletal muscle. Subsequently, Judith Treadway and
David James, also in the Ruderman group (53), showed
that the enhanced biological effects of insulin after
exercise (treadmill run for 45 min) are not paralleled
by increases in either basal or insulin-stimulated tyrosine kinase activity or autophosphorylation of the
insulin receptor. Laurie Goodyear at the Joslin Research Laboratory and colleagues (17) and Jorgen
Wojtaszewski and colleagues (57), working jointly with
Goodyear and Erik Richter, now at the Krogh Institute
in Copenhagen, extended these findings in rat and
human skeletal muscle, respectively. Paradoxically,
they found that contraction caused a decrease in insulin-stimulated tyrosine phosphorylation (by 2025%)
and insulin response sequence (IRS)-1 immunoprecipitated phosphatidylinositol 3-kinase (PI3-kinase) activity. In addition, they found that prior exercise did not
enhance the ability of insulin to induce changes in Akt
or glycogen synthase kinase (GSK)-3 in human muscle
(57). In contrast, Zhou and Dohm (59a) found that prior
exercise increases the ability of insulin to stimulate
phosphotyrosine immunoprecipitable PI3-kinase activity, and, more recently, Howlett et al. (27a), working in
the Goodyear laboratory, observed an increase in IRS2-associated PI3-kinase activity under these condi-
767
tions. Likewise, an increase in insulin-stimulated Akt

activity postexercise has been reported in mice by the
latter group (58a).
Collectively, on the basis of these findings, it is unclear whether the increased insulin action in skeletal
muscle after exercise is explained by enhanced activation of early or intermediate events in the wing of the
insulin-signaling cascade that goes through PI3-kinase. Whether exercise affects the ability of insulin to
alter an event distal to PI3-kinase or a PI3-kinaseindependent signaling mechanism remains to be determined. With respect to these possibilities, Goodyear
and co-workers (19) showed that exercise, by itself,
mimics some of the signaling changes caused by insulin in rat skeletal muscle, including activation of mitogen-activated protein kinases, Akt and p70S6K, and
inhibition of glycogen synthase kinase. In addition,
Pessin and Saltiel (43), on the basis of studies in
adipose tissue, proposed the existence of a PI3-kinaseindependent mechanism by which insulin can stimulate glucose transport. However, the relevance of these
observations to the enhanced insulin-stimulated glucose and amino acid transport after exercise in muscle
remains to be determined.
Recruitment of GLUT-4 glucose transporters to the
plasma membrane. Although exercise does not activate
the same early events in the insulin-signaling cascade
in skeletal muscle as insulin, it also stimulates glucose
uptake by enhancing the translocation of GLUT-4 glucose transporters from an intracellular location to the
cell surface. The first evidence for this was obtained
from measurements of the subcellular distribution of
GLUT-4 glucose transporters after acute exercise in
Fig. 1. Potential mechanisms by which prior exercise

via AMP-activated protein kinase (AMPK) could enhance the ability of insulin to stimulate glucose transport in skeletal muscle. The possibility that AMPK
leads to an increase in phosphatidylinositol 3-kinase
(PI3K) activity by affecting the tyrosine phosphorylation of insulin response sequence-2 is not shown. See
text for details.
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768
rat skeletal muscle by Edward Hortons group at the

University of Vermont and Harriet Wallberg-Henriksson at the Karolinska Institute of Sweden (24) and by
Holloszys laboratory working in conjunction with
Amira Klip at the University of Toronto (14). The
laboratories of Holloszy (34), Morris Birnbaum at the
University of Pennsylvania (59), and Steen Lund and
Oluf Pedersen (35) at Aarhus University Hospital in
Denmark later showed that such glucose transporter
recruitment could occur even when activation of PI3kinase, which is required for the stimulation of glucose
transport by insulin, is inhibited by wortmannin.
These important findings proved conclusively that exercise and insulin trigger GLUT-4 translocation in
muscle by effects on different signaling mechanisms.
However, they did not rule out the possibility that
insulin and exercise stimulate some common downstream signaling event.
Historically, one hypothesis put forth to explain the
postexercise increase in insulin-stimulated glucose
transport relates to the possibility that insulin and
exercise stimulate the translocation of GLUT-4 from
different pools. If this occurred, insulin could act on a
larger number of transporters after exercise or it could
act on transporters with different properties. The notion of distinct intracellular insulin- and exerciserecruitable GLUT-4 pools in skeletal muscle was first
proposed by Amira Klip and co-workers (15) at the
University of Toronto, based on analyses of isolated
intracellular membranes and plasma membranes from
control, exercised, and acutely insulin-treated rats.
Subsequent to this, Lise Coderre (10) in Paul Pilchs
laboratory at Boston University was the first to isolate
and characterize biochemically intracellular insulin
and exercise-recruitable GLUT-4 populations from rat
skeletal muscle by using fractions separated by discontinuous sucrose density-gradient centrifugation. She
found that the two transporter populations had the
same protein composition but that they differed in
their densities and sedimentation coefficients. The
most definitive evidence for distinct insulin and exercise-recruitable GLUT-4 pools, however, was reported
in 1998 by Torkil Ploug at the Muscle Research Center
of the University of Copenhagen, working in collaboration with Samuel Cushman and Evelyn Ralston at the
National Institutes of Health (44). In an elegant set of
experiments, they first demonstrated by immunofluorescence microscopy and immunogold electron microscopy that intracellular GLUT-4 vesicles are either positive or negative for the transferrin receptor. They then
proceeded to show that only the transferrin receptorpositive vesicles were recruited by contractions. Later
studies by Eva Toma s in Zorzanos laboratory at the
University of Barcelona suggested that both of these
pools (insulin and exercise) are derived from an endosomal compartment (52). Thus the evidence for distinct
exercise and insulin recruitable pools is reasonably
strong. Whether their presence will help explain the
postexercise increase in insulin-stimulated glucose
transport remains to be determined. To answer this
question will almost certainly require fundamental inJ Appl Physiol VOL
formation about the distal signals by which insulin and

exercise trigger GLUT-4 vesicle recruitment from intracellular populations, the docking of these vesicles,
and their fusion with cell surface membranes.
Finally it has also been suggested that exercise could
increase glucose uptake by enhancing the synthesis of
GLUT-4 at the level of transcription. Thus studies from
Dohms laboratory (39) have shown that a single bout
of exercise can moderately increase GLUT-4 mRNA in
previously untrained (1.4-fold) and trained rats for 3 h
(1.8-fold) after a single bout of exercise. Likewise, Ren
et al. working in Holloszys laboratory (45) found a 50%
increase in GLUT-4 protein and a twofold increase in
GLUT-4 mRNA 16 h after a single bout of swimming
exercise. Thus exercise clearly also acutely induces
signals that lead to an increased expression of GLUT-4
mRNA and protein. As with its effect on GLUT-4 translocation, the precise identity of these signals is not
known. For additional information on this and other
material covered in this section, the reader is referred to
a number of excellent recent reviews (18, 26, 30, 46, 56).
AMP-ACTIVATED PROTEIN KINASE
A major advance in understanding at a molecular

level how contraction affects glucose transport in the
muscle cell was the discovery of AMP-activated protein
kinase (AMPK). This heterotrimeric enzyme, which
contains distinct -, -, and -subunits, is regulated by
changes in a cells energy state and possibly other
factors. As first characterized in liver by David Carling
and D. Graham Hardie (21) at the University of
Dundee in Scotland, increases in the AMP-to-ATP or
creatine-to-creatine phosphate ratios of a cell, such as
those that occur in response to ischemia and other
stresses, can activate AMPK by several mechanisms.
The activation of AMPK, in turn, sets in motion a
number of events that both increase ATP generation
(e.g., increased fatty acid oxidation) and decrease ATP
utilization for processes not required for a cells immediate viability (e.g., inhibition of cholesterol and fatty
acid synthesis).
The first indication that AMPK could be involved in
the regulation of muscle metabolism was reported by
William Winder at Brigham Young University in Utah
in a joint effort with Hardie (55). They demonstrated
that treadmill running increased AMPK activity in red
quadriceps muscle of a rat by two- to threefold within 5
min. They also showed that this increase in activity
persisted for as long as the rat continued to run and
that it was associated with decreases in the activity of
acetyl-CoA carboxylase and the concentration of malonyl-CoA, an allosteric inhibitor of carnitine palmitoyl
transferase, the enzyme that controls the transfer of
long-chain fatty acyl CoA into mitochondria where they
are oxidized. Subsequently, Demetrios Vavvas and coworkers in the Ruderman laboratory (54) and Winder
et al. (55) reported similar changes in response to
muscle contraction induced by sciatic nerve stimulation. Vavvas et al. also showed that activation of
AMPK in this setting involved the 2-isoform that it
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was evident within seconds and that after 5 min of

intense contraction it could persist for 1 h.
A specific role for AMPK in the regulation of glucose
uptake was demonstrated in 1997 by Winder and coworkers (36). Using an isolated rat hindquarter preparation, they showed that perfusion with the AMPK
activator 5-aminoimidazole-4-carboxamide ribofuranoside (AICAR) increased glucose uptake by approximately twofold. Subsequent studies carried out jointly
by the Goodyear and Winder laboratories established
that this effect of AICAR was due to increased glucose
transport, that it involved GLUT-4 translocation (33),
and that, like the increase in glucose transport induced
by muscle contraction, it was not blocked when PI3kinase is inhibited by wortmannin (22). Likewise,
chronic AICAR therapy has been shown by Winders
laboratory to increase GLUT-4 protein in muscle (as
does exercise) in vivo (25). A similar effect, as well as
an increase in GLUT-4 mRNA has been demonstrated
by Holloszy et al. (41) in epitrochlearis muscle incubated for 24 h with AICAR. Despite its array effects on
GLUT-4, the precise mechanism by which AMPK activation stimulates glucose transport is still unknown.
On the other hand, the molecular events activated in a
cell by AICAR in vitro should be easier to characterize
than those induced by muscle contraction in vivo. For
this reason, AICAR or other pharmacological AMPK
activators may prove to be useful tools in determining
how prior exercise enhances insulin action in muscle.
In this context, Fisher and Nolte (16), working in
Holloszys laboratory, have recently shown that both
prior exposure to AICAR and prior tetanic contraction
enhance the ability of insulin to stimulate glucose
transport in an incubated epitrochlearis muscle. They
also found that early and intermediate events in the
insulin-signaling pathway (e.g., PI3-kinase activation)
were not involved. Thus AMPK, like exercise, appears
to work downstream or independently of PI3-kinase to
improve insulin sensitivity.
Finally, recent studies by Birnbaums laboratory (38)
have shown that expression of a dominant inhibitory
mutant of AMPK completely blocks the ability of hypoxia or AICAR to activate glucose uptake, although
only partially reducing contraction-stimulated glucose
uptake in skeletal muscle. These authors suggested
that AMPK transmits a portion of the signal by which
muscle contraction increases glucose uptake, but other
AMPK-independent pathways also contribute to the
response.
SUBJECTS FOR FURTHER STUDY
The effects of prior exercise on insulin-resistant muscle. This review has focused on the effects of an acute
bout of exercise on insulin action and signaling in
normal skeletal muscle. However, from a clinical perspective, the effects of prior exercise are most likely to
be relevant in muscle that is insulin resistant. Insulin
resistance has been defined as an impaired ability of a
given amount of insulin to exert its usual biological
effect and could be related to a decrease in insulin
J Appl Physiol VOL
769
sensitivity or responsiveness. It has long been appreciated that muscle of patients with Type 2 diabetes, or
at risk for developing it, are insulin resistant (12). It
was for this reason that regular physical activity was
first considered for the therapy and prevention of Type
2 diabetes (37, 49). Despite this, investigations of the
effect of a prior bout of exercise on insulin action in
insulin-resistant muscle have been few. A potentially
important study was carried out by Nicholas Oakes et
al. (40), working in E. W. Kraegens laboratory at the
Garvan Institute in Sydney, Australia. In rats made
insulin resistant by ingestion of a eucaloric, high-fat
diet for 3 wk, they found that a single bout of exercise
(24 h earlier) substantially reversed the impaired ability of insulin to stimulate glucose uptake into muscle
during a euglycemic hyperinsulinemic clamp. They
also found that the improvement in insulin sensitivity
after exercise was associated with decreases in the
concentrations of long-chain fatty acyl CoA and malonyl CoA. In a subsequent study, Kim Bell et al. (1) in
the same laboratory found that prior exercise also
reversed an increase in membrane-associated protein
kinase C- in muscle of fat-fed rats. Although insulin
signaling is altered in muscle of these rats (60), the
effect of exercise on these signaling abnormalities has
not been studied.
Effects of a single bout of exercise vs. those of physical
training. As already noted, the increased insulin sensitivity of muscle in physically trained humans disappears rapidly (4872 h) once they stop exercising, suggesting it is in large part related to the last bout of
physical activity. On the other hand, physical training
diminishes adiposity, fat cell size, and plasma insulin
levels (3) and increases the expression of GLUT-4 in
muscle (61), all of which could hypothetically enhance
the ability of a given amount of insulin to stimulate
glucose transport. Thus the relative importance of individual exercise bouts vs. chronic effects of physical
training in enhancing insulin action remains unsettled.
As already noted, improvements in glucose tolerance
were observed over 20 years ago in response to physical
training in patients with Type 2 diabetes. Several
years later, complete normalization of glucose tolerance and high plasma insulin levels were observed
after 1 yr of intense training by Holloszy and coworkers (27), and more recently increased physical
activity has been shown to diminish progression from
impaired glucose tolerance to Type 2 diabetes by Pan et
al. (42). Despite these impressive clinical findings, investigations of the effects of physical training on insulin signaling in muscle of trained humans and experimental animals have yielded inconsistent results. For
further discussion of the effects of physical training on
insulin action in humans and experimental animals,
and in particular subjects with Type 2 diabetes and/or
insulin resistance, the reader is referred to a number of
recent reviews (18, 26, 46, 56) and several chapters in
the recently published Handbook of Exercise in Diabetes (47a).
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Effect of exercise on cells other than those in skeletal

muscle. Another question for future study is whether
exercise enhances insulin signaling in cells other than
the skeletal muscle myocyte. Such cells could be
present in the arterial wall. Thus insulin resistance, as
manifest by impaired activation of PI3-kinase and Akt
by insulin, has been found in the aorta of a hyperinsulinemic obese fa/fa (Zucker) rat by George King and
co-workers at the Joslin Research Laboratory (31). In
addition, Yasuo Ido, David Carling, and Neil Ruderman at Boston University and Hammersmith Hospital
in England (29) have shown that the ability of insulin
to activate Akt in cultured human umbilical vein endothelial cells is depressed after 24 h of incubation in a
hyperglycemic (30 mM glucose) medium. Relevant to
this review, they found that this impairment in insulin
signaling caused by hyperglycemia was prevented
when the human umbilical vein endothelial cells were
concurrently incubated with AICAR, an activator of
AMPK. Whether exercise causes a similar increase in
AMPK in the endothelial cell, in vivo, and if so whether
this contributes to its ability to diminish cardiovascular disease in humans (47a) is clearly a subject for
further study.
CONCLUDING REMARKS
The subject of exercise and insulin signaling is somewhat unusual for a historical review, since the first key
observations are barely 20 years old and papers published in the past year are also discussed. Despite this,
it is increasingly clear that lifestyle changes that include physical activity will very likely play an increasing role in the prevention and treatment of Type 2
diabetes and other diseases associated with insulin
resistance. In addition, it is equally clear that an understanding at a molecular level (e.g., insulin signaling) of how exercise diminishes insulin resistance and
prevents cellular damage and/or dysfunction will be
critical to the success of this effort.
This work was supported in part by National Institute of Diabetes
and Digestive and Kidney Diseases Grants DK-19514 and
DK-49147, a Mentor Based Fellowship award from the American
Diabetes Association, and a Center Grant for the Study of Diabetic
Complications from the Juvenile Diabetes Research Foundation.
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J Appl Physiol 93: 773781, 2002;

10.1152/japplphysiol.00126.2002.
highlighted topics
Exercise Effects of Muscle Insulin Signaling and Action
Invited Review: Exercise training-induced changes
in insulin signaling in skeletal muscle
JULEEN R. ZIERATH
Department of Clinical Physiology, Karolinska Hospital,
Karolinska Institutet, SE-171 77 Stockholm, Sweden
Zierath, Juleen R. Invited Review: Exercise training-induced
changes in insulin signaling in skeletal muscle. J Appl Physiol 93:
773781, 2002;10.1152/japplphysiol.00126.2002.This review will provide insight on the current understanding of the intracellular signaling
mechanisms by which exercise training increases glucose metabolism
and gene expression in skeletal muscle. Participation in regular exercise
programs can have important clinical implications, leading to improved
health in insulin-resistant persons. Evidence is emerging that insulin
signal transduction at the level of insulin receptor substrates 1 and 2, as
well as phosphatidylinositol 3-kinase, is enhanced in skeletal muscle
after exercise training. This is clinically relevant because insulin signaling is impaired in skeletal muscle from insulin-resistant Type 2 diabetic
and obese humans. The molecular mechanism for enhanced insulinstimulated glucose uptake after exercise training may be partly related
to increased expression and activity of key proteins known to regulate
glucose metabolism in skeletal muscle. Exercise also leads to an insulinindependent increase in glucose transport, mediated in part by AMPactivated protein kinase. Changes in protein expression may be related
to increased signal transduction through the mitogen-activated protein
kinase signaling cascades, a pathway known to regulate transcriptional
activity. Understanding the molecular mechanism for the activation of
insulin signal transduction pathways after exercise training may provide
novel entry points for new strategies to enhance glucose metabolism and
for improved health in the general population.
AMP-activated protein kinase; diabetes; gene expression; insulin receptor substrates; mitogen-activated protein kinase; phosphatidylinositol
3-kinase
EXERCISE TRAINING: A PHYSIOLOGICAL TOOL TO
ENHANCE INSULIN ACTION
People with non-insulin-dependent Type 2 diabetes

mellitus are characterized by impaired insulin action
on whole body glucose uptake, partly owing to impaired insulin-stimulated glucose transport in skeletal
muscle (98, 99). Defects in insulin action on glucose
uptake in skeletal muscle from Type 2 diabetic patients
have been linked to impaired signal transduction (7,
Address for reprint requests and other correspondence: J. R. Zierath, Dept. of Clinical Physiology and Integrative Physiology, Karolinska Institutet, von Eulers vag 4, II, SE-171 77 Stockholm, Sweden
(E-mail: juleen.zierath@fyfa.ki.se).
http://www.jap.org
43). Insulin sensitivity has been shown to be related to

the degree of physical activity (64); therefore, physical
training programs may offer a physiological means to
improve insulin action in some insulin-resistant people. Exercise training improves glucose tolerance and
insulin action in insulin-resistant humans (35, 59) or
Type 2 diabetic patients (63, 74). The molecular mechanism for enhanced glucose uptake with exercise training may be related to increased expression and/or activity of key signaling proteins involved in the
regulation of glucose uptake and metabolism in skeletal muscle (Fig. 1). For example, exercise training leads
to increased expression of glucose transporter 4
(GLUT-4) content in skeletal muscle, and this has been
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INVITED REVIEW
Fig. 1. Exercise training-induced changes

in insulin signaling in skeletal muscle. Insulin signal transduction though the insulin receptor, insulin receptor substrate
(IRS)-1/2 and phosphatidylinositol 3-kinase (PI3-kinase) is enhanced in skeletal
muscle in the hours after an exercise bout.
These changes may enhance insulin sensitivity, as well as regulate gene expression
after exercise. Immediately after exercise,
mitogen-activated protein kinase (MAPK)
signaling to downstream substrates is enhanced, providing a possible molecular
mechanism for exercise-induced transcriptional regulation in skeletal muscle. Acute
exercise also increases AMP-activated protein kinase (AMPK) activity, leading to
changes in glucose uptake and gene expression. Exercise training is associated
with changes in mRNA of several components of insulin and MAPK signaling cascades. The master regulator(s) of exercise-responses on gene expression has not
been completely defined.
correlated with improved insulin action on glucose

metabolism (10, 14, 29, 35, 57). However, emerging
evidence suggests that these exercise-training-induced
improvements in glucose uptake are not limited to
changes in GLUT-4 expression. The improvements in
insulin sensitivity after exercise training may be related to changes in expression and/or activity of proteins involved in insulin signal transduction in skeletal
muscle. This review will focus on effects of exercise on
insulin signaling in skeletal muscle. Emphasis will be
placed on studies whereby insulin signaling was measured several hours after an acute exercise bout or
after a period of exercise training.
EARLY STEPS IN INSULIN SIGNAL TRANSDUCTION
The insulin receptor is a heterotetrameric membrane glycoprotein composed of two -subunits and two
-subunits, linked together by disulfide bonds (reviewed in Ref. 77). Insulin binds to the extracellular
-subunits, and this leads to activation of the transmembrane -subunits and autophosphorylation of
the receptor. Multiple tyrosine phosphorylation sites
present on the -subunit of the insulin receptor play
important functional roles in promoting receptor kinase activity, mediating differential responses along
mitogenic and metabolic pathways, and facilitating the
interaction between the receptor and intracellular substrates. In recent years, research efforts have largely
moved from studies designed to characterize insulin
binding and receptor function to studies oriented toward the identification and characterization of postreceptor molecular targets that regulate insulin signal
transduction to different metabolic and mitogenic responses. Although the picture is far from complete,
some important early steps in insulin signaling have
emerged.
J Appl Physiol VOL
Insulin receptor substrates. Insulin signaling is a

complex series of events involving multiple effector
proteins that orchestrate diverse cellular responses.
Importantly, insulin signaling pathways are not necessarily linear, as there is a high degree of cross talk
between the signal transducers. Insulin receptor substrate isoforms (IRS-1 to -4) (46, 47, 69, 70), Gab-1 (30),
and Cbl (58) link the initial event of insulin receptor
signaling cascade to downstream events. IRS molecules contain multiple tyrosine phosphorylation sites
that become phosphorylated after insulin stimulation
(reviewed in Refs. 77, 79) and bind downstream signaling molecules containing src homology 2 domains.
IRS-1 and IRS-2 play selective roles in the regulation
of metabolic and mitogenic responses in insulin-sensitive tissues, including skeletal muscle, adipose tissue,
and liver. IRS-3 and IRS-4 are not expressed in skeletal muscle; therefore, these substrates will not be reviewed. Likewise, because of the paucity of data concerning the role of Gab-1 and Cbl in mediating insulin
signaling to glucose transport after exercise in skeletal
muscle, these substrates will not be reviewed.
Tissue-specific roles of IRS-1 and IRS-2 have been
elucidated through studies performed with different
knockout strategies in mice. IRS-1 appears to be the
predominant isoform mediating signal transduction in
skeletal muscle (2, 71), whereas IRS-2 appears to be
important in -cell development (80). Both isoforms
are important for regulation of metabolism in liver
(36). Although different IRS proteins clearly have selective roles in mediating many of metabolic and mitogenic responses, a degree of redundancy in the function
may exist. For example, in skeletal muscle and adipose
tissue from Type 2 diabetic subjects, insulin-mediated
tyrosine phosphorylation of IRS-1 is impaired, whereas
IRS-2 phosphorylation is normal (7, 43, 60). Thus IRS
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INVITED REVIEW
molecules are likely to play complementary roles in the

mediation of insulin action.
Phosphatidylinositol 3-kinase and downstream effectors. Phosphatidylinositol 3-kinase (PI3-kinase) is one
of the most characterized intermediate effector molecules that associate with IRSs. PI3-kinase associates
with tyrosine phosphorylated IRSs after insulin stimulation and catalyzes the formation of phosphatidylinositol-3,4,5-trisphosphate, which serves as an allosteric regulator of phosphoinositide-dependent kinase
(1). PI3-kinase plays an important role in the acute
effect of insulin on glucose transport and GLUT-4
translocation in skeletal muscle (49, 65, 92). Because
several reviews in this series will consider molecular
mechanisms by which insulin or exercise mediate
GLUT-4 translocation and glucose transport, this aspect will not be considered in depth in the present
review. The downstream effectors of PI3-kinase that
signal to glucose transport have not been fully elucidated. PI3-kinase presumably mediates glucose transport via signaling to protein kinase B (PKB)/Akt and/or
protein kinase C (PKC)- (reviewed in Ref. 77). Tissue
culture systems or animal models in which either signaling via AKT/PKB (11) or PKC- (4, 41) has been
disrupted suggest that these targets partly contribute
to the regulation of glucose uptake, although other
intermediates are likely to participate (58). Through
comparative genomics and pathway analysis, new
downstream components of the insulin pathway are
likely to be identified.
EFFECTS OF EXERCISE TRAINING
ON INSULIN SIGNALING
Immediately after an acute bout of exercise, glucose

transport in skeletal muscle is increased through an
insulin-independent translocation of GLUT-4 to the
cell surface (18, 42, 49). Thus immediate effects of
acute exercise on glucose homeostasis occur primarily
at the level of GLUT-4 traffic rather than through
enhanced insulin signaling at the level of the insulin
receptor, IRS-1, IRS-2, or PI3-kinase (34, 48, 49, 66, 73,
8688, 92, 97). Several hours after acute exercise, a
persistent increase in insulin sensitivity of glucose
transport occurs in skeletal muscle. Effects of exercise
can be observed even 16 h after the last exercise
session (10, 57). Measurements made at this time may
reflect changes in protein expression (enhanced or suppressed) that occur in response to the exercise bout.
Exercise training increases insulin-mediated whole
body glucose disposal (15, 16, 32, 35). This effect is
correlated with increased protein expression of
GLUT-4 (10, 15, 32, 35, 56, 57, 94), as well as with
adaptive responses in expression and function of key
insulin-signaling molecules (10, 33, 40, 94). Although
our understanding of the signaling pathways regulating glucose metabolism is limited, studies designed to
examine the effects of exercise training on known constitutes of the insulin signaling pathway are emerging.
Insulin receptor substrates. IRS-1 and IRS-2 are important signal transducers in skeletal muscle. Exercise
J Appl Physiol VOL
training-induced effects on IRSs have been elucidated.

In rodents, long-term endurance training (5 bouts/wk
for 9 wk) increased insulin receptor and IRS-1 mRNA
in skeletal muscle 48 h after the last bout of exercise
(37). In contrast, insulin receptor and IRS-1 mRNA
was not altered after short-term endurance training in
humans (60 min/day for 9 days) (78). However, complementary studies of protein expression were not performed in either of these studies (37, 78). Consistent
with this finding in humans, IRS-1 protein expression
is not increased 16 h after short-term endurance training in rats (6 h/day for 1 or 5 days) (10). In this model,
insulin-stimulated tyrosine phosphorylation of IRS-1
tended to be increased after 1 day of exercise. The
increase in IRS-1 tyrosine phosphorylation correlated
with increased insulin receptor tyrosine phosphorylation (10). Surprisingly, IRS-1 protein expression was
reduced 16 h after 5 days of exercise, despite a profound increase in insulin-stimulated IRS-1 tyrosine
phosphorylation. The reduction in IRS-1 protein expression in exercise-trained rodents is similar to the
55% reduction in IRS-1 protein expression in skeletal
muscle obtained 48 h after exercise from subjects engaged in habitual training programs (running 50
km/wk for 2 mo) (94). Major effects of exercise training on insulin signaling do not include transcriptional
activation of the IRS-1 gene. Rather, improvements in
insulin action after exercise training are likely to occur
from more efficient signaling per molecule of IRS-1,
leading to increased signal transduction to downstream substrates.
Exercise training has differential effects on protein
expression of IRS-1 and IRS-2. In rat epitrochlearis
muscle, 16 h after an acute 6-h swim bout, IRS-2
expression is increased threefold (10). In this model,
IRS-2 expression is restored to pretraining levels in
muscle studied 16 h after 5 days of repeated 6-h swim
bouts. Thus increased IRS-2 protein expression partly
accounts for increased insulin action in skeletal muscle
after exercise. In support of this hypothesis, mRNA
levels of IRS-2 in human skeletal muscle increase transiently 3 h after a single exercise bout, but this effect is
diminished after short-term (9 days) endurance training (78). The initial observation that exercise increases
insulin action at the level of IRS-2 was confirmed with
IRS-2 knockout mice (34). In wild-type mice, insulinmediated IRS-2 tyrosine phosphorylation was increased in skeletal muscle immediately after exercise,
with no effect noted in IRS-2 null mice (34). Although
IRS-2 protein expression was not assessed, increased
protein expression of IRS-2 is not likely to account for
enhanced tyrosine phosphorylation after exercise.
Thus exercise has multiple effects on IRS-2 that involve changes in signal transduction and protein expression. Immediately after exercise, insulin-mediated
IRS-2 tyrosine phosphorylation is enhanced. In the
hours after an acute exercise bout, IRS-2 undergoes a
rapid upregulation at the level of mRNA and protein.
The enhanced insulin action on IRS-2 is maintained for
at least 16 h after exercise. Detailed time-course studies of the effects of exercise on either signal transduc-
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INVITED REVIEW
tion or protein expression of IRS-2 have not been performed in human subjects or in rodents. However, in
people engaged in habitual exercise (long-distance running) programs, IRS-2 protein expression in skeletal
muscle obtained 48 h after the last bout of exercise is
decreased compared with levels measured in sedentary
individuals (94). Thus repeated exercise may be associated with either increased degradation or decreased
synthesis of IRS-2. The physiological role for IRS-2 in
mediating insulin signaling in skeletal muscle after
exercise is unknown.
PI3-kinase. Insulin-stimulated PI3-kinase activity is
impaired in skeletal muscle from Type 2 diabetic and
obese insulin-resistant subjects (7, 24, 39, 43), thus
constituting a pivotal site of insulin resistance. Several
hours after acute exercise, a persistent increase in
insulin sensitivity of glucose transport occurs in skeletal muscle. Enhanced phosphotyrosine-associated
PI3-kinase activity (34, 88, 97) in the hours after exercise may partly contribute to the persistent increase in
glucose uptake after exercise. Regular exercise training enhances insulin-stimulated PI3-kinase activity in
skeletal muscle (10, 33, 40). Because PI3-kinase is an
important regulatory step for glucose transport, increased signal transduction at this key step after exercise training may contribute to the exercise-associated
increase in insulin action in skeletal muscle. Increased
mRNA levels of the p85 -subunit of PI3-kinase have
been noted in rodents and humans engaged in acute
(78) or long-term (38) exercise training; however, the
physiological significance of this is unknown, because
overexpression of the p85 -subunit in L6 myotubes is
associated with decreased, rather than increased, insulin-stimulated glucose uptake (75). Thus enhanced
insulin-stimulated PI3-kinase activity, rather than
changes in expression of the subunits of the enzyme, is
likely to account for enhanced glucose metabolism after
exercise.
Several studies have now been performed to determine the effects of exercise training on insulin-mediated PI3-kinase activity in skeletal muscle. In rodents,
insulin-stimulated IRS-associated PI3-kinase activity
is markedly increased in isolated epitrochlearis muscle
studied 16 h after 1 or 5 days of prior exercise (6-h
swim bouts) (10). This positive effect on insulin signaling occurs despite reduced IRS-1 protein expression.
Importantly, the increased insulin-stimulated IRS-1associated PI3-kinase activity after exercise training
corresponds with an increase in insulin-stimulated
3-O-methylglucose transport activity (10). These findings in rodents can be translated to humans. In
healthy young, but sedentary, men, 7 days of exercise
training [60 min/day at 75% maximal oxygen consump O2 max)] is associated with increased insulin sention (V
sitivity and enhanced insulin-stimulated phosphotyrosine-associated PI3-kinase activity in skeletal
muscle (33). Because time course studies reveal that
both insulin action on anti-phosphotyrosine- and insulin action on IRS-1-associated PI3-kinase activity occur
in parallel (43), IRS-1 is likely to be the predominant
J Appl Physiol VOL
tyrosine-phosphorylated molecule transmitting this

exercise-mediated change in insulin signaling to PI3kinase in human skeletal muscle. Consequently,
changes in phosphotyrosine-associated PI3-kinase activity in human muscle after exercise training (33) are
likely to represent increased IRS-1-associated PI3-kinase activity. Consistent with this observation, a subsequent study provided evidence that insulin-stimulated IRS-1-associated PI3-kinase activity is greater in
skeletal muscle from subjects engaged in habitual ex O2 max of 56.1 2.5 ml/kg)
ercise training programs (V
O2 max of 44.4
compared with sedentary subjects (V
2.7 ml/kg) (40). When exercise-trained and sedentary
subjects were compared together, PI3-kinase activation was correlated with both glucose disposal and
O2 max (40). Collectively, these results are consistent
V
with the notion that regular exercise training leads to
improvements in glucose disposal through enhanced
insulin signaling at the level of PI3-kinase.
Insulin-stimulated IRS-2 associated PI3-kinase is
also increased after exercise training. However, IRS-1
and IRS-2 undergo differential regulation in skeletal
muscle in response to exercise (10). The increase in
IRS-2 protein expression in rat epitrochlearis muscle
noted 16 h after a 6-h exercise bout was associated with
enhanced basal and insulin-stimulated IRS-2-associated PI3-kinase activity. In contrast to findings for
IRS-1, in which protein levels were decreased with
exercise training, IRS-2 protein expression and IRS-2associated PI3-kinase activity normalized to sedentary
levels after 5 days of exercise (10). Thus IRS-1 and
IRS-2 are likely to have specialized rather than redundant roles in mediating insulin signal transduction in
skeletal muscle in response to exercise training. This
finding is further reinforced in studies whereby insulin
signaling immediately after exercise has been examined in IRS-2 knockout mice (34). In IRS-2-deficient
mice, the increase in insulin-stimulated phosphotyrosine-associated PI3-kinase activity immediately after an acute treadmill running was attenuated compared with that in wild-type mice, suggesting that
IRS-2 signaling can partly account for the increase in
phosphotyrosine-associated PI3-kinase activity after
exercise. However, insulin-stimulated 2-deoxyglucose
uptake in skeletal muscle measured after exercise was
not different between IRS-2-deficient and wild-type
mice. Thus the exercise effect on IRS-2 may be masked
in the presence of normal levels of IRS-1. Alternatively,
another undefined tyrosine-phosphorylated protein
may contribute to insulin-mediated glucose uptake in
IRS-2-deficient skeletal muscle (34). The physiological
significance of the exercise-induced IRS-2 signaling
awaits further elucidation.
AMP-ACTIVATED PROTEIN KINASE
AMP-activated protein kinase (AMPK) has been implicated as an important mediator of muscle contraction-induced glucose transport (84) and a target for
pharmacological intervention to treat altered glucose
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homeostasis associated with Type 2 diabetes and obesity

(51). AMPK is a heterotrimeric protein, composed of one
catalytic () and two noncatalytic ( and ) subunits (84)
and is activated by cellular stress associated with ATP
depletion (26). Although AMPK activity does not appear
to be increased in response to insulin, some discussion of
this kinase is warranted in the present review as it has
been implicated to be one of several critical regulators of
mitogenic and metabolic events in response to exercise in
skeletal muscle. For example, an increase in AMPK activity in response to muscle contraction or exercise has
been correlated with GLUT-4 translocation and glucose
transport in skeletal muscle (5, 6, 26, 27, 45, 50). Furthermore, increased AMPK activity has also been correlated with increased free fatty acid oxidation in skeletal
muscle (6), decreased lipogenesis and lipolysis in adipocytes (68), and decreased free fatty acid and cholesterol
synthesis in hepatocytes (28). Thus recent evidence is
consistent with the hypothesis that AMPK plays a central role in the regulation of glucose homeostasis in response to exercise.
Exercise-mediated changes in AMPK activity. Isoform-specific and exercise intensity-dependent changes
in AMPK activity have been observed in skeletal muscle (21, 89). Low- to moderate-intensity aerobic exercise induces an isoform-specific and intensity-dependent increase in AMPK 2 but not in AMPK 1 activity
in moderately trained subjects (21, 89). However, in
response to anaerobic sprint exercise, activity of AMPK
1 and 2 are both increased (9). These exercise-intensity differences may be related to the finding that
AMPK complexes containing the 2-isoform rather
than the 1-isoform have a greater dependence on AMP
(9, 62). Although these studies do not directly link
activation of AMPK to increased glucose uptake, direct
evidence can be acquired from studies in transgenic
animal models. Transgenic overexpression of a dominant inhibitory mutant of AMPK in skeletal muscle
completely blocks the ability of hypoxia to activate
glucose uptake, whereas only partially reducing contraction-stimulated glucose uptake (52). Thus AMPKdependent and AMPK-independent pathways contribute to the regulation of glucose uptake in skeletal
muscle in response to exercise. For example, in rats,
glucose transport in slow-twitch muscle can be markedly activated in response to contraction, without measurable changes in AMPK activity (17). Collectively,
these studies illustrate the complexity in identifying
the precise role of the AMPK pathway in regulating
metabolic events, and they strongly suggest that additional factors contribute to the regulation of exercisemediated glucose uptake. However, the latter studies
do not distract from the attractiveness of AMPK as a
target for exercise-induced glucose transport and a
candidate for pharmacological intervention to improve
glucose homeostasis.
AMPK and metabolic disease. Because AMPK appears to increase glucose metabolism by insulin-independent signaling cascades (27), activation of this
pathway provides an alternative strategy to increase
glucose transport in insulin-resistant skeletal muscle.
J Appl Physiol VOL
An obvious hypothesis to consider is whether pharmacological intervention of AMPK with compounds designed to mimic the exercise response on glucose uptake or fatty acid oxidation may be efficacious in the
management of metabolic abnormalities associated
with Type 2 diabetes mellitus. One compound commonly utilized to test this hypothesis is 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR). AICAR is
an adenosine analog that can be taken up into intact
hepatocytes, adipocytes, and skeletal muscle and can
be phosphorylated to form 5-aminoimidazole-4-carboxamide ribonucleotide, the monophosphorylated derivative that mimics the effects of AMP on AMPK without
affecting ATP or ADP content. In isolated epitrochlearis muscle incubated in serum, AICAR exposure leads
to an increase in insulin sensitivity that appears to
mimic an exercise response (20).
AICAR effects on whole body glucose homeostasis
have been determined in diabetic rodents. Treatment
of diabetic ob/ob (67) or KKAy-CETP (19) mice with
AICAR lowers blood glucose and insulin concentration
and improves glucose tolerance. Furthermore, in vitro
exposure of isolated skeletal muscle to AICAR elicits a
normal increase in glucose transport in insulin-resistant ob/ob mice (67). This is consistent with studies in
Type 2 diabetic subjects whereby exercise is reported to
elicit a normal increase in AMPK 2 activity in skeletal
muscle (53). These studies provide evidence to suggest
that exercise-induced AMPK activity and AICARinduced AMPK activity are not impaired in insulinresistant skeletal muscle. However, AICAR treatment
of ob/ob (67) and KKAy-CETP (19) mice is associated
with a worsening of the blood lipid profile. Because
AICAR is a nonspecific AMPK activator (12, 76), longterm exposure to AICAR may trigger effects other than
activation of AMPK in either liver or adipose tissue
and this may influence plasma lipid mobilization. In
this respect, the recent work from Moller and colleagues (95) is important to emphasize, as they have
identified AMPK as the elusive target of metformin, further highlighting the importance of AMPK in the regulation of glucose homeostasis and providing proof of
concept that activation of this target can enhance insulin
sensitivity, as metformin is a widely used drug for treatment of Type 2 diabetes mellitus. Through use of a novel
AMPK inhibitor, AMPK activation was shown to be required for metformins inhibitory effect on glucose production by hepatocytes. Furthermore, incubation of isolated epitrochlearis muscle with metformin resulted in
an increase in the activity of both catalytic subunits of
AMPK, coincident with an increase in glucose uptake.
These findings (95) have important clinical implications
because metformin also increases insulin-stimulated glucose transport in skeletal muscle from Type 2 diabetic
subjects (22, 23).
MECHANISMS FOR INCREASED PROTEIN EXPRESSION
IN SKELETAL MUSCLE AFTER EXERCISE
Mitogen-activated protein kinase signaling. One future direction will be the identification of pathways
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that regulate gene expression in skeletal muscle after

exercise. Clearly, multiple mechanisms contribute to
the regulation of insulin action and protein expression.
Recent evidence suggests that mitogen-activated protein kinase (MAPK) signaling cascades may constitute
one important cellular signaling mechanism mediating
exercise-induced adaptations in skeletal muscle.
MAPK activation has been implicated as an important
mechanism governing cellular proliferation and differentiation in many cell types (reviewed in Ref. 55).
Although the possible involvement of MAPK signal
transduction pathways in exercise-mediated regulation of gene expression in skeletal muscle has been
considered in detail (reviewed in Ref. 82), a brief review is warranted.
Members of the MAPK family form at least three
parallel signaling cascades that include the extracellular-regulated protein kinase (ERK1/2 or p42 and p44
MAPK), p38 MAPK, and c-Jun NH2 kinase. Evidence
is emerging that MAPK signaling pathways are directly activated in human skeletal muscle in response
to acute, short-term exercise (3, 44, 81, 83) or endurance running (8, 93). Activity of several downstream
substrates of ERK and p38 MAPK signaling cascades,
such as MAPK-activated protein kinase (MAPKAPK) 1
and 2, as well as the mitogen and stress-activated
kinase (MSK) 1 and 2, are increased immediately after
acute sprint (44) or endurance exercise (93). Substrate
specificity for MAPK signaling cascades has been determined with an ex vitro system to achieve contraction (electrical stimulation) of isolated rat epitrochlearis muscle, combined with the use of chemical
inhibitors of ERK and p38 MAPK (61). Thus contraction-induced inductions of MAPKAPK1 and MAPKAPK2 occur via separate pathways, reflecting ERK
and p38 MAPK stimulation, respectively. In contrast,
induction of MSK1 and MSK2 requires simultaneous
activation of ERK and p38 MAPK (61). The direct link
between MAPK activation and changes in gene expression in skeletal muscle after exercise has yet to be
established, as the majority of studies to address this
point have been correlative (reviewed in Ref. 82). Future work directed toward understanding whether exercise-induced MAPK signaling directly suppresses or
enhances gene expression is necessary.
AMPK signaling. AMPK has been proposed to regulate gene expression (25). This may be partly through
direct targeting of AMPK complexes containing the
2-isoform to the nucleus (62). AMPK is involved in
transcriptional regulation by repressing genes involved in glucose signaling in hepatocytes (62, 90) and
upregulating genes involved in glucose uptake and
substrate metabolism in skeletal muscle (31, 54, 85).
For example, activation of AMPK mimics several classic exercise-mediated responses on gene expression,
including increases in GLUT-4 mRNA and protein content, hexokinase II mRNA and activity, uncoupling
protein-3 mRNA, mitochondrial enzymes, and glycogen
content in skeletal muscle (31, 54, 85, 96). These
changes can also be observed in skeletal muscle from
diabetic rodents. Hexokinase II and GLUT-4 protein
J Appl Physiol VOL
expressions, as well as in vitro MEF2 sequence-specific

binding activity, are increased in skeletal muscle from
lean and ob/ob mice after 7 days of AICAR treatment
(67), presumably through increased AMPK activity. A
similar increase in MEF2 sequence-specific binding
activity has also been observed in human skeletal
muscle after marathon running (93). Thus increased
MEF2 sequence-specific binding activity may confer
exercise-specific changes in gene expression. Consistent with this hypothesis, the MEF2 site appears to be
essential for GLUT-4 expression, because deletions or
point mutations within the MEF2 consensus binding
sequence of the human GLUT-4 promoter completely
prevent tissue-specific and hormonal/metabolic regulation of GLUT-4 (72).
Cross talk between MAPK and AMPK signaling pathways. AMPK may activate other downstream effectors
such as p38 MAPK and mitogen-activated protein kinase kinase 3 (91). For example in clone 9 cells, activation of p38 was reported to be required for AICARstimulated glucose transport, because treatment of the
cells with the p38 inhibitor SB-203580 or overexpression of dominant-negative p38 mutant inhibited glucose transport (91). Thus AICAR-mediated activation
of glucose transport in clone 9 cells involves AMPK
signaling to p38. Future work aimed to determine
whether there is similar cross talk between AMPK
and MAPK pathways in skeletal muscle will be important to understand the nature of signals that lead to
changes in gene expression in response to exercise.
Identification of AMPK and MAPK substrates that
activate or repress specific genes should reveal important regulatory mechanisms controlling protein expression in skeletal muscle.
SUMMARY AND FUTURE DIRECTIONS
Exercise training appears to enhance insulin sensitivity by increased postreceptor insulin signaling. Increased insulin-mediated glucose transport appears to
be related to enhanced signal transduction at the level
of IRS proteins and PI3-kinase. These findings are
clinically relevant because insulin-stimulated tyrosine
phosphorylation of IRS-1 and activity of PI3-kinase are
reduced in skeletal muscle from Type 2 diabetic patients (7, 13, 43). Thus exercise training may be one
therapeutic strategy to restore impaired insulin signal
transduction in skeletal muscle from Type 2 diabetic
patients.
Because the insulin-signaling pathway(s) to glucose
transport has not been fully elucidated, a more complete mapping of the necessary and required components of this network is required. Identification of
intermediates in the insulin signaling pathway may be
achieved through comparative genomics, using genetically modified model organisms, combined with bioinformatic approaches to identify mammalian homologues for pathway analysis. Studies with ex vivo
models and chemical inhibitors may directly link insulin signaling and MAPK or AMPK pathways to
changes in gene expression in response to exercise
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training. Transgenic and knockout mice in which components of insulin signaling and MAPK or AMPK cascades have been overexpressed or ablated will reveal
the requirements for these signaling intermediates in
exercise-mediated responses. Knowledge of the human
genome sequence, used in concert with gene and/or
protein array technology, will provide a powerful
means to facilitate efforts in revealing molecular targets that regulate glucose homeostasis in response to
exercise training. This will also offer quicker ways
forward to identifying gene expression profiles in insulin-sensitive and insulin-resistant human tissue and
may by useful to identify biochemical entry points for
drug intervention to improve glucose homeostasis.
This review was supported by grants from the Swedish Medical
Research Council, Swedish Diabetes Association, Swedish National
Centre for Research in Sports, and Novo-Nordisk Foundation.
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J Appl Physiol 93: 782787, 2002;

10.1152/japplphysiol.01266.2001.
highlighted topics
Exercise Effects on Muscle Insulin Signaling and Action
Invited Review: Regulation of skeletal muscle GLUT-4
expression by exercise
G. LYNIS DOHM
Department of Biochemistry, Brody School of Medicine,
East Carolina University, Greenville, North Carolina 27858
Dohm, G. Lynis. Invited Review: Regulation of skeletal muscle
GLUT-4 expression by exercise. J Appl Physiol 93: 782787, 2002;
10.1152/japplphysiol.01266.2001.The amount of GLUT-4 protein is a
primary factor in determining the maximal rate of glucose transport into
skeletal muscle. Therefore, it is important that we understand how
exercise regulates GLUT-4 expression so that therapeutic strategies can
be designed to increase muscle glucose disposal as a treatment for
diabetes. Muscle contraction increases the rates of GLUT-4 transcription
and translation. Transcriptional control likely requires at least two DNA
binding proteins, myocyte enhancer factor-2 and GLUT-4 enhancer factor, which bind to the promoter. Increased GLUT-4 expression may be
mediated by the enzyme AMP-activated kinase, which is activated during exercise and has been demonstrated to increase GLUT-4 transcription. Further research needs to be done to investigate whether AMPactivated kinase activates myocyte enhancer factor-2 and GLUT-4
enhancer factor to increase transcription of the GLUT-4 gene.
glucose transporter-4 promoter; myocyte enhancer factor-2; adenosine
5-monophosphate kinase; transgenic mice
GLUCOSE TRANSPORT INTO SKELETAL muscle is primarily

mediated by a membrane-associated glucose transport
protein termed GLUT-4. Under normal resting conditions, most of the GLUT-4 molecules reside in membrane vesicles inside the muscle cell. In response to
insulin or muscle contraction, GLUT-4 translocates to
the cell membrane where it inserts to increase glucose
transport.
The amount of GLUT-4 protein is a primary factor in
determining the maximal rate of glucose transport into
skeletal muscle (32). Because skeletal muscle is an
important tissue in maintaining postprandial glucose
homeostasis, increasing GLUT-4 protein is a potential
method to treat the hyperglycemia associated with
diabetes. We and others (6, 15, 18, 50, 53) have shown
that exercise can increase the content of muscle
GLUT-4. Therefore, it is important that we understand
how exercise regulates GLUT-4 expression so that
Address for reprint requests and other correspondence: G. L.

Dohm, Dept. of Biochemistry, Brody School of Medicine, East Carolina Univ., Greenville, NC 27858 (E-mail: dohmg@mail.ecu.edu).
782
therapeutic strategies might be designed to help increase muscle glucose disposal as a treatment for diabetes. In this review, the mechanisms that may be
involved in regulating GLUT-4 expression are examined.
CHANGES IN MUSCLE GLUT-4 IN RESPONSE
TO STIMULI
Changes in GLUT-4 expression in response to exercise can be rather rapid. In rats, 1 day after swimming
for 6 h, there was a twofold increase in GLUT-4 mRNA
and a 1.5-fold increase in GLUT-4 protein (51). On the
second day after swimming, muscle GLUT-4 protein
was twofold higher than in sedentary controls. After
termination of swim training, rat muscle GLUT-4 protein returned to control levels by 40 h (22) or 90 h (31).
These studies suggest that GLUT-4 has a short halflife, and its expression can be changed rapidly. GLUT-4
expression can be induced by short-term, high-intensity, intermittent training (fourteen 20-s exercise
bouts/day for 8 days) or low-intensity, prolonged exercise training (total exercise time of 360 min/day for 8
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INVITED REVIEW
days) (55). Like exercise training, electrical stimulation also increases muscle GLUT-4 content (13, 20). In
contrast to swimming exercise, GLUT-4 content was
not elevated until 5 days of electrical stimulation (20).
Several studies have confirmed that muscle GLUT-4 is
increased by exercise training in humans (23, 26, 37,
38). Seven days of strenuous cycling resulted in a
threefold increase in muscle GLUT-4 (24). There is
some controversy as to how long the elevated GLUT-4
persists after training is terminated (25, 61).
Paradoxically, eccentric exercise has been shown to
decrease muscle GLUT-4 in both men (1) and rats (2).
Eccentric contractions caused GLUT-4 to decrease,
whereas concentric contractions and passive stretch of
the muscle had no effect (33). Unaccustomed eccentric
contractions produce muscle damage and soreness. Repair of the damaged tissue leads to a much different
response in the regulation of GLUT-4 expression than
does normal exercise (34).
In contrast to exercise, forced chronic physical inactivity (16) or limb immobilization (12, 49) in rats causes
muscle GLUT-4 to be decreased. Immobilization of
human vastus muscle as a result of casting also decreased muscle GLUT-4 by 50% after 1 wk of inactivity,
and the level remained decreased at 6 wk of casting (4).
Surprisingly, inactivity caused by hindlimb suspension
of rats caused the opposite effect with increased
GLUT-4 (expressed per milligram of total protein) in
the atrophied muscle (19, 27).
Denervation by sectioning of a nerve, such as the
sciatic or peroneal, is often used as a model for muscle
inactivity. Muscle GLUT-4 protein and mRNA are decreased in denervated rat (5) and rabbit (8) muscle.
Direct electrical stimulation of rabbit tibialis anterior
muscle protected GLUT-4 mRNA levels against the
effect of denervation (8). An interesting study was
performed by Chilibeck et al. (9) to confirm these findings in human subjects. They performed functional
electrical stimulation cycle ergometer training on individuals with motor-complete spinal cord injury.
GLUT-4 protein was increased by 72% with training.
The results of Megeney et al. (39, 41) argue that the
denervation effect is not simply due to the lack of
muscle activity. GLUT-4 was measured at different
time points after the sciatic nerve was sectioned at
different locations. GLUT-4 decrements occurred more
rapidly in denervated muscles with a short nerve
stump than in those with a long nerve stump, suggesting that neurogenic factor(s) released from the nerve
influences GLUT-4 expression. In a second study, they
treated muscles with tetrodotoxin, which blocks the
propagation of action potentials along the sciatic nerve,
but axonal transport is maintained. GLUT-4 mRNA
was depressed in the denervated muscle but not in the
tetrodotoxin-treated muscle, suggesting again that
neurogenic factors were regulating GLUT-4 expression.
In rat muscle, GLUT-4 protein and glucose transport
are markedly higher in red-oxidative (type I and IIA
fibers) muscle fibers than in white-glycolytic fibers
(type IIB) (32, 40). This might be an important factor in
J Appl Physiol VOL
the adaptation to exercise, because endurance training

results in a shift from type IIB to type IIA fibers.
However, in human skeletal muscle, there is a much
smaller difference in GLUT-4 expression in different
muscle fiber types (10, 17). Daugaard et al. (10) isolated individual muscle fibers and typed them according to myosin isoform. GLUT-4 was 20% higher in
fibers expressing myosin heavy chain I than in those
expressing myosin heavy chain IIA or IIX. No difference could be detected between IIA and IIX fibers.
After 2 wk of exercise training, GLUT-4 was increased
by 23% in type I muscles, but there were no changes
in type IIA or IIX. However, the low-intensity exercise
that was used is known to recruit primarily type I
fibers.
Hormones also regulate muscle glucose transporter
protein concentration. GLUT-4 expression was increased by insulin (28) and thyroid hormone (57) and
decreased by elevated cAMP (28, 60). Regulation of
GLUT-4 expression by contractile activity is independent of hormonal regulation, because treadmill running increased GLUT-4 in streptozotocin diabetic rats
(30). The effects of insulin-deficiency and denervation
on GLUT-4 concentrations were additive. Physical
training also increases muscle GLUT-4 protein and
mRNA in patients with Type 2 diabetes (11). These
results suggest that muscle contractile activity directly
modulates muscle GLUT-4 expression, independent of
insulin action.
REGULATION OF MUSCLE GLUT-4 EXPRESSION
To understand the mechanisms that increase muscle

GLUT-4 mRNA and protein in response to exercise, we
investigated whether the rate of GLUT-4 transcription
was increased. Nuclei were isolated from muscle of rats
after a single bout of exercise or after the last bout of
treadmill training, and GLUT-4 transcription was determined by nuclear run-on analysis. Transcription
was unaltered 30 min after the last exercise bout, was
increased 1.8-fold after 3 h, and returned to control
values by 24 h (44). This suggests that there is a rapid
but transient activation of gene transcription. Further
evidence that GLUT-4 gene transcription is increased
by exercise was provided from studies of transgenic
mice carrying the human GLUT-4 (hGLUT-4) promoter linked to a chloramphenacol acetyl transferase
(CAT) reporter gene (36). Transgenic mice were treadmill exercised, and CAT mRNA was increased 12 h
after the end of the exercise bout. These results demonstrate that there is an exercise response element in
the GLUT-4 promoter that drives gene transcription in
response to exercise.
Kuo et al. (35) provided evidence that translation of
the GLUT-4 message is also regulated by exercise.
They found that polysome-associated GLUT-4 mRNA
was increased immediately after exercise and remained significantly increased for the first 5 h of recovery. Polysome-associated mRNA is considered to be
translationally active mRNA. Therefore, GLUT-4 ex-
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INVITED REVIEW
pression may be regulated at both the transcriptional

and translational level.
Transcription of a gene is usually regulated by DNA
sequences in a promoter that is 5 upstream of the
initiation site. With the use of muscle cell culture
experiments, it was recently reported (54) that the rat
promoter has an 82-bp muscle-specific enhancer (between 502 and 420 bp from the initiation start site)
that is active in both cardiac and skeletal muscle. The
GLUT-4 enhancer relies on the concerted interaction
among the transcription factors MyoD and myocyte
enhancer factor-2 (MEF-2) and the thyroid receptor-1
to produce full expression.
Transgenic mice with various portions of the
hGLUT-4 promoter fused to a reporter gene, such as
the CAT gene, have been used to identify DNA sequences in the promoter of the GLUT-4 gene that
regulate transcription. When active portions of the
GLUT-4 promoter are present, the mice express reporter mRNA. By using this approach, it was found
that 895 bp of the hGLUT-4 promoter were sufficient
to provide tissue-specific expression, i.e., GLUT-4 was
expressed only in adipose tissue, heart, and skeletal
muscle. In addition, this promoter construct demonstrated normal regulation in diabetic animals (insulin
deficient). A deletion or mutation of the MEF-2 binding
domain of the GLUT-4 promoter ablated transgene
expression in all tissues (46, 56). By using isoformspecific antibodies in electrophoretic mobility shift assays, MEF-2A and MEF-2D isoforms were shown to
bind the GLUT-4 MEF-2 binding domain in skeletal
muscle (46, 56). Mora and Pessin (43) demonstrated
that the MEF-2A-MEF-2D heterodimer is responsible
for hormonally regulated expression of the GLUT-4
gene. Recently, Michael et al. (42) reported that expression of the transcriptional regulator peroxisome proliferator-activated receptor- coactivator-1 (PGC-1) in L6
cells causes the total restoration of GLUT-4 mRNA
levels to those observed in vivo. Because PGC-1 is a
coactivator of MEF-2C, it seems likely that regulation
may require the concerted action of transcription factors and coactivators.
Oshel et al. (47) described another putative transcription factor, called GLUT-4 enhancing factor
(GEF), that is important in the regulation of GLUT-4
gene expression. GEF binds to DNA sequences in a
region designated domain 1 (724 bp to 712 bp from
the initiation start site). Deletion of domain 1 completely eliminated expression of GLUT-4 in muscle.
These results demonstrate that MEF-2 and GEF binding domains must function together for proper expression and regulation of the GLUT-4 gene. Oshel et al.
speculated that regulated and tissue-specific expression of the GLUT-4 gene occurs only in tissues in which
sufficient GEF binding activity and MEF-2 binding
activity coincide. Regulation of the GLUT-4 gene under
an insulin-deficient condition may reflect the levels of
either GEF binding activity, or MEF-2 binding activity,
or an interaction of the two sites.
Utilizing transgenic mice carrying the hGLUT-4/
CAT gene, we investigated regulation of the GLUT-4
J Appl Physiol VOL
promoter in muscle during exercise. A single bout of

exercise increased endogenous muscle GLUT-4 mRNA
with a peak at 12 h after the end of exercise (36). Mice
with 895 bp of the hGLUT-4 promoter demonstrated
an increase in CAT mRNA in muscle that also peaked
at 12 h after exercise. In contrast, CAT was not increased by exercise in mice with 730 bp of the
GLUT-4 promoter. This regulation is very similar to
that reported by Oshel et al. (47) and suggests that
MEF-2 and GEF may be involved in upregulating the
GLUT-4 gene in response to exercise. Interestingly,
denervation caused GLUT-4 and CAT mRNAs to be
depressed in mice with the 730-bp promoter construct (29), demonstrating that regulation of expression in denervated muscle is different than that for
exercise (or lack of exercise).
Ezaki (14) investigated regulation of the mouse
GLUT-4 promoter. He found that 1,000 bp of the promoter provided the DNA sequences required for the
appropriate tissue-specific and metabolic regulation of
GLUT-4 expression. In contrast to results with the
hGLUT-4 promoter, he found that the MEF-2 binding
site was not necessary for expression of GLUT-4 in
murine muscle. The exercise response element was
found to be between 1,000 bp and 423 bp from the
start site (58, 59). In agreement with the results with
the human promoter (36), the DNA sequences required
for GLUT-4 regulation by denervation were different
from those for exercise (59) and lay between 423 bp
and the initiation start site. A representation of the
regulatory elements within the hGLUT-4 promoter are
shown in Fig. 1.
SIGNALS FOR REGULATION OF GLUT-4 EXPRESSION
DURING EXERCISE
To understand regulation of GLUT-4 expression, we

must know the changes during exercise that activate
transcription factors to turn on the muscle GLUT-4
gene. One signaling candidate is muscle high-energy
phosphates, which decline during exercise. Evidence
for the role of energy charge in transcriptional regulation came from a study in which GLUT-4 protein and
high-energy phosphate levels were shown to be inversely correlated in electrically stimulated muscles
(64). Depleting muscle creatine phosphate by feeding
rats a creatine analog also caused muscle GLUT-4
protein to be increased (52), further suggesting a relationship between a decrease in high-energy phosphates
and increased GLUT-4 expression.
A likely link between energy charge and regulation
of gene transcription is the enzyme AMP-activated
protein kinase (AMPK). AMPK is activated during
exercise and has been termed a master metabolic
switch because it phosphorylates key target proteins
that control flux through metabolic pathways (62). It is
also related to SNR1 protein in yeast, which is known
to regulate gene expression. Chronic activation of
AMPK by injection of the adenosine analog 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) caused
GLUT-4 protein to be increased in muscle (21). Interest-
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INVITED REVIEW
Fig. 1. Representation of the important response elements in the human GLUT-4 promoter. GEF, binding site for
the GLUT-4 enhancer factor; MEF-2, binding site for myocyte enhancer factor-2; TRE, binding site for thyroid
hormone receptor-. Promoter sequences within 895 bp of the start site contain sufficient information for the
correct tissue expression of GLUT-4 and for regulation by exercise, insulin, 5-aminoimidazole-4-carboxamideribonucleoside (AICAR), and denervation. If either the MEF-2 or GEF binding site is mutated, there is no GLUT-4
expression in muscle. Deletion of DNA between 526 and 712 bp did not alter GLUT-4 expression or regulation.
The 730-bp promoter (contains a partial GEF binding site) demonstrates low-level expression of GLUT-4 in
muscle with regulation by denervation, but not by exercise, insulin, or AICAR.
ingly, the greatest increase was found in white muscle

fibers, and there was no GLUT-4 induction by AICAR in
soleus muscle (7, 65). AICAR treatment also reversed the
decline in GLUT-4 protein in all denervated muscles
except the soleus (48). In vitro incubation of epitrochlearis muscles with AICAR also increased GLUT-4 expression, demonstrating that the effect was a direct activation
of expression in the muscle (45).
Using transgenic mice carrying the hGLUT-4 promoter/CAT gene, we demonstrated that AICAR increases GLUT-4 transcription (65). As with exercise,
the transgene with 895 bp of the promoter regulated
in a manner similar to that of the endogenous gene, but
this regulation was lost with the 730-bp promoter.
This suggests that exercise and AICAR activate the
same transcription factors to increase GLUT-4 expression. Because MEF-2 and GEF are known to be important transcription factors for the regulation of the
GLUT-4 gene, we measured the effect of AICAR on the
DNA binding of these two proteins. AICAR increased
MEF-2 binding, whereas GEF binding to DNA was
slightly reduced, suggesting that these transcription
factors may be involved in regulating GLUT-4 gene
transcription in response to exercise and AMP activation.
It has recently been shown that chronic activation of
AMP kinase also leads to activation of DNA binding by
the transcription factor called nuclear respiratory factor-1 (NRF-1) (3). NRF-1 is important in the regulation
of mitochondrial biogenesis and transcription of respiratory enzymes. Because the expression of mitochondrial enzymes and GLUT-4 is increased by exercise
and AICAR treatment, it is possible that the NRF-1
might also play a role in GLUT-4 expression.
Another attractive signaling candidate for regulation of GLUT-4 gene expression during exercise is
calcium, which is released during the contraction cycle.
Wu et al. (63) recently demonstrated that MEF-2 is
activated in muscle by a calcineurin-dependent pathway. Calcineurin is a calcium-activated phosphatase,
and its activity correlates with expression of endogeJ Appl Physiol VOL
nous genes that are transcriptionally activated by muscle contractions. It could be speculated that GLUT-4
expression may be regulated by calcineurin activation
of MEF-2.
FUTURE RESEARCH QUESTIONS
The content of GLUT-4 protein in muscle is an important determinant of glucose homeostasis, and the
effectiveness of exercise in the treatment of diabetes
may relate to the increase in muscle GLUT-4. Therefore, research needs to be done to discover the mechanisms that regulate muscle GLUT-4.
One fertile area of investigation is the signal that
turns on the GLUT-4 gene. Hormones, such as insulin
and thyroid hormone, induce gene expression, but their
concentrations do not change in concert with the
changes in GLUT-4 during exercise. In addition, muscle contraction and one-legged exercise both increase
muscle GLUT-4 without changes in hormones. Thus
the signal is most logically a substance that has altered
concentration in muscle during exercise. As discussed
above, Ca2 and AMP are good candidates for signaling during exercise, because their intracellular concentrations increase during exercise. In addition, both
molecules are activators of kinases and/or phosphatases, which would provide a pathway for the regulation of transcription factors. One approach to the study
of these signaling pathways will be to utilize transgenic and knockout mice that overexpress or ablate the
Ca2- and AMP-related kinases and phosphatases.
Another area of research interest is the transcription
factors that are turned on by the signals generated in
muscle during exercise. As indicated above, MEF-2 and
GEF are candidates that have been identified so far.
However, the involvement of coactivators, such as
PGC-1, and the interaction of other transcription factors, such as myoD and thyroid hormone receptors,
may make understanding the regulation of GLUT-4
expression a challenge.
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It is important that we continue to study the regulation of muscle GLUT-4 expression. If we understand
how exercise regulates the gene, we may then be able
to devise pharmacological interventions that would
increase muscle GLUT-4 and provide a treatment for
the hyperglycemia of diabetes.
18.
19.
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10.1152/japplphysiol.01219.2001.
highlighted topics
Exercise Effects of Muscle Insulin Signaling and Action
Invited Review: Effects of acute exercise and
exercise training on insulin resistance
ERIK J. HENRIKSEN
Muscle Metabolism Laboratory, Department of Physiology, University of Arizona
College of Medicine, Tucson, Arizona 85721-0093
Henriksen, Erik J. Invited Review: Effects of acute exercise and
exercise training on insulin resistance. J Appl Physiol 93: 788796, 2002;
10.1152/japplphysiol.01219.2001.Insulin resistance of skeletal muscle
glucose transport is a key defect in the development of impaired glucose
tolerance and Type 2 diabetes. It is well established that both an acute
bout of exercise and chronic endurance exercise training can have beneficial effects on insulin action in insulin-resistant states. This review
summarizes the present state of knowledge regarding these effects in the
obese Zucker rat, a widely used rodent model of obesity-associated
insulin resistance, and in insulin-resistant humans with impaired glucose tolerance or Type 2 diabetes. A single bout of prolonged aerobic
exercise (3060 min at 6070% of maximal oxygen consumption) can
significantly lower plasma glucose levels, owing to normal contractioninduced stimulation of GLUT-4 glucose transporter translocation and
glucose transport activity in insulin-resistant skeletal muscle. However,
little is currently known about the effects of acute exercise on muscle
insulin signaling in the postexercise state in insulin-resistant individuals. A well-established adaptive response to exercise training in conditions of insulin resistance is improved glucose tolerance and enhanced
skeletal muscle insulin sensitivity of glucose transport. This traininginduced enhancement of insulin action is associated with upregulation of
specific components of the glucose transport system in insulin-resistant
muscle and includes increased protein expression of GLUT-4 and insulin
receptor substrate-1. It is clear that further investigations are needed to
further elucidate the specific molecular mechanisms underlying the
beneficial effects of acute exercise and exercise training on the glucose
transport system in insulin-resistant mammalian skeletal muscle.
skeletal muscle glucose transport; obese Zucker rat; impaired glucose
tolerance; Type 2 diabetes
NUMEROUS METABOLIC AND HEMODYNAMIC factors can contribute to the improvements in glucose homeostasis
that are seen after acute exercise and exercise training
in individuals with insulin resistance. These adaptive
responses include enhanced insulin action on the
skeletal muscle glucose transport system, reduced hormonal stimulation of hepatic glucose production, improved blood flow to skeletal muscle, and normaliza-
Address for reprint requests and other correspondence: E. J. Henriksen, Dept. of Physiology, Ina E. Gittings Bldg. 93, Univ. of Arizona, Tucson, AZ 85721-0093 (E-mail: ejhenrik@u.arizona.edu).
788
tion of an abnormal blood lipid profile. This minireview will focus only on the adaptive responses to
exercise of the glucose transport system in skeletal
muscle. In this context, one purpose of this article is to
examine the present body of knowledge regarding the
influence of a single bout of prolonged aerobic [3060
min at 6070% of maximal oxygen consumption
O2 max)] exercise on whole-body glucose tolerance and
(V
on insulin-stimulated skeletal muscle glucose transport activity in conditions of insulin resistance. Moreover, this document will briefly review the effects of
endurance exercise training on the skeletal muscle
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INVITED REVIEW
glucose transport system in insulin-resistant states,

with a particular emphasis on the beneficial adaptive
responses of the protein expression and functionality of
insulin signaling factors and of GLUT-4 protein to this
intervention. Because of space limitations, coverage
will be restricted to the obese Zucker (fa/fa) rat, a
widely used rodent model of obesity-associated insulin
resistance, and to insulin-resistant humans with impaired glucose tolerance (IGT) or Type 2 diabetes.
these insulin-independent mechanisms (see Refs. 43,

53, and 98 for reviews). Whereas relatively little is
currently known about the specific intracellular factors
that allow muscle contractions to stimulate GLUT-4
translocation and glucose transport in skeletal muscle,
recent evidence supports a role of the activation of
5-adenosine monophosphate-activated protein kinase
(AMP kinase), an enzyme activated by a decrease in
cellular energy charge (80).
REGULATION OF SKELETAL MUSCLE

GLUCOSE TRANSPORT
DEVELOPMENTAL ASPECTS OF INSULIN RESISTANCE
Skeletal muscle, which makes up 40% of the body

mass of humans and other mammalian species, is the
primary tissue responsible for the peripheral disposal
of glucose in response to a glucose or insulin challenge
or during an exercise bout (6, 24). Glucose transport
into the myocyte is acutely regulated by insulin and
insulin-like factors through the activation of a series of
intracellular proteins (for a review of insulin signaling
and glucose transport activation, see Refs. 103 and
117). Insulin binding to the -subunit of the insulin
receptor causes an enhancement of the tyrosine kinase
activity of the intracellular -subunits, leading to autophosphorylation of the insulin receptor and to tyrosine phosphorylation of insulin receptor substrate-1
(IRS-1). The tyrosine-phosphorylated IRS-1 molecule
can then dock with the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3-kinase), which in turn
activates the p110 catalytic subunit of this enzyme.
PI3-kinase catalyzes the production of phosphoinositide moieties, which can subsequently activate 3phosphoinositide-dependent kinases (PDK), including
PDK1. A downstream target of PDK1 is Akt/protein
kinase B (Akt/PKB), a serine/threonine kinase. Several
lines of investigation support a role of Akt/PKB in the
regulation of glucose transport (44, 77, 112), although
other studies indicate that Akt/PKB is not involved in
this process (76). Clearly, the exact role of Akt/PKB in
the glucose transport process in skeletal muscle remains to be defined. The activation of these steps
ultimately results in the translocation of a regulatable
glucose transporter protein isoform (GLUT-4) to the
sarcolemmal membrane and the t tubules, where glucose transport takes place via a facilitative diffusion
process. GLUT-4 is only one of several isoforms in a
family of facilitative glucose transporter proteins, and
available evidence supports the idea that it is the
magnitude of GLUT-4 translocation that dictates the
capacity of a skeletal muscle to enhance glucose transport activity (53).
Glucose transport into skeletal muscle is also stimulated by an insulin-independent mechanism that is
activated by contractions (54, 87), hypoxia (3, 15, 16),
nitric oxide (5, 94), and bradykinin (83, 107). The
translocation mechanism for increasing plasma membrane GLUT-4 also functions in response to contractions (37, 41), hypoxia (15), nitric oxide (33), and bradykinin (2, 107). It is likely that there is an important
role of Ca2 in the activation of glucose transport by
J Appl Physiol VOL
Insulin resistance of skeletal muscle glucose transport represents a major defect in the normal maintenance of euglycemia (117). This insulin resistance is
frequently accompanied by a variety of metabolic and
cardiovascular abnormalities, including hypertension,
glucose intolerance, Type 2 diabetes, dyslipidemia,
atherosclerosis, and central obesity, a condition referred to as syndrome X (92, 93) or the insulin
resistance syndrome (23). The link among these disorders has been attributed to hyperinsulinemia, a consequence of the insulin resistance (23).
The obese Zucker (fa/fa) rat is an animal model of
severe skeletal muscle insulin resistance that is also
characterized by marked hyperinsulinemia, glucose intolerance, dyslipidemia, and central adiposity (84) and
therefore is a suitable animal model of the insulin
resistance syndrome. GLUT-4 protein expression in
skeletal muscle of the obese Zucker rat is generally not
defective (Refs. 35, 36, 63; but also see Ref. 52). However, insulin-stimulated GLUT-4 protein translocation
(35, 74) and glucose transport activity (21, 35, 49) are
substantially impaired in isolated skeletal muscle from
these obese animals. Anai et al. (1) demonstrated that
in skeletal muscle from the obese Zucker rat there are
significant defects in crucial aspects of the insulin
signaling cascade. In hindlimb muscle from insulinresistant obese Zucker rats, IRS-1 protein expression is
60% less and insulin-stimulated IRS-1 tyrosine phosphorylation is 38% less, despite elevated basal levels,
than in muscle from age-matched, insulin-sensitive
lean Zucker rats. The amount of the p85 regulatory
subunit of PI3-kinase associated with the tyrosinephosphorylated IRS-1 in the insulin-stimulated state is
29% of lean control levels. Finally, IRS-1-associated
PI3-kinase activity in muscle immunoprecipitates from
these obese animals is only 54% of the level observed in
lean animals (1).
Similar findings have been made in skeletal muscle
from insulin-resistant humans. Insulin resistance in
Type 2 diabetes, except for that observed in morbidly
obese humans (29), is not generally associated with a
decreased skeletal muscle level of GLUT-4 protein
(117). However, insulin stimulation fails to induce normal GLUT-4 protein translocation to the sarcolemma
in skeletal muscle from subjects with Type 2 diabetes
(99, 116). Moreover, Goodyear et al. (40) and Bjo rnholm et al. (10) demonstrated that significantly less
insulin stimulation of insulin receptor and IRS-1 tyrosine phosphorylation and of IRS-1-immunoprecipi-
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INVITED REVIEW
table PI3-kinase activity is detected in muscle from

insulin-resistant subjects compared with insulin-sensitive controls. In addition, insulin-stimulated Akt/
PKB kinase activity is significantly reduced in skeletal
muscle from insulin-resistant Type 2 diabetic subjects
(79), although this is not a consistent finding (72).
Insulin-stimulated glycogen synthase activity is generally reduced (Refs. 7, 19, 109; but also see Ref. 78), and
the reduction in nonoxidative glucose disposal in these
individuals is thought to be secondary to defects in
glucose transport (19). No reduction in insulin-stimulated mitogen-activated protein kinase (MAP kinase)
phosphorylation is detected in incubated muscle preparations from Type 2 diabetic subjects (78). Therefore,
there are marked defects in specific signaling proteins
and in GLUT-4 protein translocation that define the
insulin-resistant state.
PREMISE FOR EXERCISE AS AN INTERVENTION IN
INSULIN RESISTANCE
It is well established that acute physical activity and

endurance exercise training lead to enhancements of
insulin-mediated glucose metabolism in healthy individuals and in normal rodent models (see reviews in
Refs. 43, 45, 5, and 62). In normal rodent models,
moderate- or high-intensity exercise training can improve glucose tolerance (9, 64), whole body insulin
sensitivity (65, 66), and insulin action on skeletal muscle glucose transport (48, 96, 97, 105). The protein
expression of GLUT-4 appears to play an important
role in the capacity of a skeletal muscle for insulin
stimulation of glucose transport (47, 69). The increased
insulin action on skeletal muscle glucose transport
after exercise training is associated with increased
GLUT-4 protein expression (42, 48, 88, 96, 97, 101,
105), as well as adaptive responses of enzymes involved
in glucose phosphorylation and oxidation (summarized
in Refs. 53 and 62). On the bases of these observations,
exercise represents an important potential intervention for improving the metabolic status of insulinresistant individuals.
An improvement in insulin action on skeletal muscle
glucose metabolism in insulin-resistant individuals
could decrease conversion rates to overt diabetes, as
well as reduce cardiovascular mortality. Indeed, the
results of the recently concluded Diabetes Prevention
Program in the United States convincingly demonstrated that the introduction of a lifestyle modification
program, including at least a 7% reduction in body
weight and a minimum of 150 min of physical activity
per week, could, over a 3-yr period, reduce the incidence of Type 2 diabetes by 58% in individuals at
significant risk for the development of the disease (28).
These results are essentially identical to those from a
recent Finnish study in which a weight-loss and exercise intervention reduced the incidence of Type 2 diabetes in overweight men with IGT (111) and are consistent with earlier epidemiological studies indicating
that increased physical activity can prevent the development of Type 2 diabetes in men (46).
J Appl Physiol VOL
ACUTE EXERCISE AND INSULIN RESISTANCE
Glucose tolerance and glucose disposal. The various

metabolic responses to a single bout of exercise performed by insulin-resistant rodents (primarily the
obese Zucker rat) and humans are summarized in
Tables 1 and 2, respectively. An acute bout of exercise
O2 max) by untrained rats does not
(30 min at 70% of V
improve intravenous glucose tolerance (64). Likewise,
a single bout of prolonged aerobic exercise (3060 min at
O2 max) will normally not improve the di6070% of V
minished glucose tolerance of insulin-resistant Type 2
diabetic subjects, as evaluated with a standard oral
glucose tolerance test (95). In contrast, a prior bout of
prolonged moderate-intensity exercise (45 min of cycle
O2 max) performed by Type 2
ergometry at 45% of V
diabetic subjects can reduce the glycemic excursions
and elevated plasma insulin levels during the 4-h period after a breakfast meal containing 56% carbohydrate, 30% fat, and 14% protein (81). Interestingly, this
exercise effect was not observed when a lunch meal
was subsequently consumed 4 h after the breakfast
meal (81), indicating the transient nature of this acute
exercise effect.
It is, however, well established that, during a single
bout of physical activity, a significant glucose-lowering
effect in obese rodents (38) and in Type 2 diabetic
individuals can be elicited (58, 81, 86, 114). Plasma
insulin is also reduced in these individuals during the
exercise bout (86). Whole body glucose disposal during
a euglycemic, hyperinsulinemic clamp can also be enhanced in obese rats after a single bout of exercise (14,
38, 89) and is associated with an increase in insulinstimulated glucose transport in skeletal muscle (89).
The effect of acute exercise on glycemia is likely due to
the ability of contractile activity to activate skeletal
muscle glucose transport, as this pathway appears to
be normal in animal models of insulin resistance (11,
12, 30, 49, 73) or in Type 2 diabetic subjects (3, 68). In
addition, the enhanced glucose transport activity resulting from the exercise bout by Type 2 diabetic humans persists into the immediate postexercise period
(27, 58, 85) and is associated with enhanced insulin
sensitivity immediately after (85) and 20 h after (27)
exercise. At 24 h after exercise, the enhanced insulin
sensitivity was not observed (22). The mechanisms for
these responses of Type 2 diabetic subjects to acute
exercise are currently unknown.
Skeletal muscle glucose transport and insulin signaling. One underlying cellular mechanism for this glucose-lowering effect of acute exercise in insulin resistance has been addressed in a study of exerciseinduced GLUT-4 translocation in a cohort of Type 2
diabetic individuals (68). Immediately after a single
bout of exercise (4560 min of cycling at 6070% of
O2 max), there was a 74 20% increase in plasma
V
membrane GLUT-4 protein in vastus lateralis muscle,
which was nearly identical to the postexercise increase
(71 18%) seen in nondiabetic subjects. Protein expression of GLUT-4 was not enhanced by this single
bout of exercise (68). Consistent with this finding are
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INVITED REVIEW
the results of King et al. (73), which demonstrated that

the exercise-induced translocation of glucose transporter protein in skeletal muscle of the obese Zucker
rat was not different from that in lean animals. Therefore, a single bout of moderate-intensity exercise can
increase muscle glucose transport via a normal induction of GLUT-4 translocation into the plasma membrane (68, 73).
The longer term effect of a single bout of exercise on
insulin signaling in insulin-resistant skeletal muscle is
less definitive. Twenty-four hours after a single exercise session (1 h of cycle ergometer exercise at 65% of
O2 max) performed by Type 2 diabetic subjects, the
V
response to insulin of skeletal muscle tyrosine phosphorylation of the insulin receptor and of IRS-1 was
significantly enhanced (22). However, insulin stimulation of IRS-1-associated PI3-kinase activity was not
enhanced by the prior exercise, and at this time point
whole body insulin-stimulated glucose disposal (assessed with a euglycemic, hyperinsulinemic clamp)
was not increased relative to the sedentary state (22).
It is clear that further investigations, incorporating
shorter postexercise time points, are needed to elucidate the mechanisms whereby acute exercise can augment skeletal muscle glucose uptake by insulin-resistant skeletal muscle.
Table 2. As mentioned previously, one characteristic

feature of the abnormal metabolic state of obese Zucker
rats is glucose intolerance. In one of the first investigations of the potential beneficial effects of exercise
training that used this animal model of obesity-associated insulin resistance, Becker-Zimmermann et al. (8)
demonstrated that mild exercise training (treadmill
running) by older (25-wk-old) obese Zucker rats could
significantly improve glucose disposal during an oral
glucose tolerance test and reduce the exaggerated insulin response to a glucose challenge. Moreover, these
investigators showed that exercise training by younger
(7-wk-old) obese Zucker rats could prevent the deterioration of glucose tolerance experienced by these animals as they develop into adulthood (8). This exercise
training-induced improvement in the whole body insulin sensitivity of obese Zucker rats was soon confirmed
with swim training (113). Several subsequent investigations also demonstrated that the impaired whole
body glucose tolerance (20, 100, 106) and the reduced
insulin sensitivity at the whole body (20, 52, 100, 106)
and hindlimb (primarily skeletal muscle) levels (60, 61,
115) of the obese Zucker rat can be substantially improved by aerobic exercise training.
The impaired whole body glucose metabolism in humans with IGT or Type 2 diabetes can likewise be
beneficially modified by exercise training (67). Endurance exercise training leads to improvements in glucose tolerance (59, 95) and whole body insulin-mediated glucose disposal (25) in insulin-resistant subjects
with IGT or Type 2 diabetes. Interestingly, Eriksson et
al. (32) reported that a chronic circuit training regimen, in which resistance-type exercises are performed,
CHRONIC EXERCISE AND INSULIN RESISTANCE
Glucose tolerance and glucose disposal. The adaptive

responses of whole body and skeletal muscle glucose
metabolism to an increase in physical activity by insulin-resistant rodents are shown in Table 1, and those
observed in insulin-resistant humans are displayed in
Table 1. Summary of effects of acute exercise or exercise training on whole body glucose disposal and skeletal
muscle insulin action in insulin-resistant rodent models
Response to
Acute Exercise
Reference
Response to
Exercise Training
Reference
64
8, 20, 100, 106
1
1
14, 38, 89
89
1
1
1
ND
73
1
1
52
4, 13, 20, 34, 60, 61, 100,
106, 115
13, 34
4, 13, 34, 36, 52, 100,
104, 106
Whole body glucose tolerance

postexercise, ivGTT or OGTT
Whole body glucose disposal
Insulin-stimulated skeletal muscle
glucose transport
GLUT-4 translocation
GLUT-4 expression
Insulin-stimulated insulin receptor
Protein expression
Tyrosine phosphorylation
ND
ND
7
1
7
52, 102
52
18
Insulin-stimulated IRS-1
Protein expression
ND
ND
1
1
7
102
52
18
ND
ND
7
7
52, 102
18
ND
ND
7
7
52
18, 52
Insulin-stimulated PI3-kinase
Protein expression
Activity
Insulin-stimulated Akt/PKB
Protein expression
Serine phosphorylation
Changes due to the exercise intervention are relative to the sedentary, insulin-resistant control groups and are either no change (7), an
increase (1), or a decrease (2). ND, not determined; ivGTT, intravenous glucose tolerance test; OGTT, oral glucose tolerance test; IRS-1,
insulin receptor substrate-1; PI3-kinase, phosphatidylinositol 3-kinase; PKB, protein kinase B.
J Appl Physiol VOL
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Table 2. Summary of effects of acute exercise or exercise training on whole-body glucose disposal and skeletal
muscle insulin action in insulin-resistant humans
Whole body glucose tolerance

Postexercise, OGTT
Postexercise, breakfast meal
Whole body glucose disposal
Insulin-stimulated skeletal muscle
glucose transport
GLUT-4 translocation
GLUT-4 expression
Insulin-stimulated insulin receptor
Protein expression
Insulin-stimulated IRS-1
Protein expression
Insulin-stimulated PI3-kinase
Protein expression
Activity
Insulin-stimulated Akt/PKB
Protein expression
Serine phosphorylation
Response to
Acute Exercise
Reference
Response to
Exercise Training
7
1
7
95
81
27, 58, 85
1
ND
1
59, 95
1
1
7
27, 58, 85
68
68
1
1
1
91
ND
26, 55, 57, 59
ND
1
22
ND
ND
ND
1
22
ND
ND
ND
7
22
ND
7
108
ND
7
108
ND
ND
Reference
25, 32, 59
Changes due to the exercise intervention are relative to the sedentary, insulin-resistant control groups and are either no change (7), an
increase (1), or a decrease (2).
also enhances insulin-mediated whole-body glucose

disposal in insulin-resistant subjects with IGT.
Skeletal muscle glucose transport and insulin signaling. Several investigations have convincingly shown
that skeletal muscle is the primary cellular locus for
the beneficial adaptive responses of whole body insulin
sensitivity to exercise training by the obese Zucker rat.
Moderate- and high-intensity aerobic training results
in an increased maximal aerobic capacity (20, 100, 106,
110) and in greater locomotor skeletal muscle levels of
enzymes involved in glucose catabolism (e.g., hexokinase and citrate synthase) (4, 13, 20, 100, 106, 110).
The enhanced exercise training-induced glucose tolerance and glucose disposal in the obese Zucker rat are
primarily due to adaptations in the insulin-dependent
glucose transport system in skeletal muscle. Exercise
training leads to enhanced insulin action on glucose
transport in locomotor muscles of the perfused hindquarter (4, 13, 20, 60, 61, 115) and in isolated, incubated locomotor skeletal muscles (34, 100, 106). Two
critical adaptive responses that underlie the enhanced
insulin-stimulated glucose transport activity after exercise training in these animals are an upregulation of
GLUT-4 protein expression (4, 13, 34, 36, 52, 100, 104,
106) and increased GLUT-4 translocation (13) and cell
surface GLUT-4 (34) after insulin stimulation.
Exercise training of animals with normal insulin
signaling leads to an enhancement of specific steps in
the insulin signaling cascade, including increased
mRNA and protein expression and functionality of the
insulin receptor, IRS-1, PI3-kinase, and MAP kinase
[extracellular-regulated kinase 1 (ERK1)] (17, 70, 71).
However, much less is known regarding the adaptive
responses to exercise training of the insulin signaling
pathway in muscle of the obese Zucker rat. Exercise
training of these insulin-resistant animals leads to
J Appl Physiol VOL
upregulation of insulin receptor tyrosine phosphorylation (52) and enhanced IRS-1 protein expression (102)
with no alteration in protein expression of insulin
receptor -subunit (52, 102), the p85 subunit of PI3kinase (52, 102), or Akt/PKB (52). However, in a recent
study by Christ et al. (18), 7 wk of exercise training by
obese Zucker rats did not cause any increases in insulin action on insulin receptor or IRS-1 tyrosine phosphorylation, PI3-kinase activity, or Akt/PKB serine
phosphorylation.
Muscle contractions lead to activation of ERK1/2, isoforms of MAP kinase (39), and there is speculation that
increases in MAP kinase signaling may be associated
with several exercise-associated adaptive responses in
skeletal muscle (82, 98). Interestingly, exercise training
by obese Zucker rats leads to upregulation of ERK2
protein expression (90). This finding raises the intriguing
possibility that enhanced signal transduction through
the MAP kinase signaling cascade may play an important role in the increased expression of glucose catabolic
enzymes, GLUT-4, and insulin signaling proteins after
exercise training by the obese Zucker rat.
Our knowledge of the underlying mechanisms for the
beneficial effects of exercise training on insulin-resistant human skeletal muscle is much less extensive.
Endurance exercise training also leads to improvements in insulin action on skeletal muscle glucose
metabolism in insulin-resistant human subjects with
IGT (95) or Type 2 diabetes (59, 95). Six weeks of
exercise training by insulin-resistant offspring of human Type 2 diabetic subjects was associated with an
enhancement of insulin-stimulated glucose transport
and phosphorylation in skeletal muscle (91). As in
rodent models of insulin resistance, an important molecular mechanism for the adaptive response to training by middle-aged men (55, 57) and by human Type 2
93 AUGUST 2002
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793
INVITED REVIEW
diabetic subjects (26, 59) is the upregulation of GLUT-4

protein expression in skeletal muscle. Whether exercise training can enhance insulin-stimulated GLUT-4
translocation in insulin-resistant human muscle is not
presently known.
Exercise training by insulin-sensitive humans results in upregulation of insulin-stimulated PI3-kinase
activity, both in longitudinal (56) and in cross-sectional
(75) studies. These studies support a role of altered
protein expression and functionality of insulin signaling factors in the enhanced insulin sensitivity of human skeletal muscle after exercise training. However,
it has recently been shown that 1 wk of exercise training (60 min/day at 70% of peak oxygen consumption)
did not enhance insulin stimulation of PI3-kinase activity or Akt/PKB activity in vastus lateralis muscle of
middle-aged men (58 yr old and presumably insulin
resistant) (108). Other potential adaptive responses of
the insulin signaling cascade in insulin-resistant skeletal muscle to regular exercise are currently unknown.
EXERCISE AND INSULIN RESISTANCE:
FUTURE DIRECTIONS
The beneficial effects of an acute bout of exercise and

of chronic exercise training on insulin action in insulinresistant states are well established. However, there
is a relative paucity of information on the specific
molecular mechanisms in the skeletal muscle glucose
transport system to explain these exercise effects. How
contractile activity by skeletal muscle causes an enhancement of insulin sensitivity is not clear. Particularly intriguing is the very recent finding that components of the kallikrein-kininogen system may play a
role in the development of enhanced insulin sensitivity
after contractions by muscles from insulin-sensitive
rats (31). This information is especially relevant in
light of findings that treatment of insulin-resistant
obese Zucker rats with bradykinin, a product of the
kallikrein-kininogen system, can enhance whole body
glucose tolerance (50) and insulin action on skeletal
muscle glucose transport (50, 51). An important area of
future investigation would be the potential interactions between products of the kallikrein-kininogen system, including bradykinin, and insulin signaling factors in insulin-resistant skeletal muscle.
A critical aspect that must be addressed in future
investigations is a better understanding of the underlying mechanisms for upregulation of GLUT-4 protein
and of specific insulin signaling factors after exercise
training by insulin-resistant rodent models, such as
the obese Zucker rat, and by humans with IGT and
Type 2 diabetes. Specifically, the potential roles of
increased intracellular Ca2 and Ca2-activated pathways, such as the MAP kinase pathway, and of a
chronically altered energy charge, such as the activation of AMP kinase, in these exercise training-induced
responses in insulin-resistant skeletal muscle require
further investigation. The elucidation of these mechanisms will assist clinicians and exercise physiologists
in the design of the most effective exercise regimens for
J Appl Physiol VOL
the improvement of insulin action in insulin-resistant

human subjects with IGT and Type 2 diabetes.
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J Appl Physiol 93: 765772, 2002;

(9) in 1887 reported that when a

CHAUVEAU AND KAUFMAN

Address for reprint requests and other correspondence: N. B.

and of the signaling changes induced in muscle by

The first clue that exercise might enhance the ability

8750-7587/02 $5.00 Copyright 2002 the American Physiological Society

whole body and presumably muscle insulin sensitivity,

Table 1. Glucose utilization by the isolated perfused

Values are means SE; n no. of observations. Hindquarters

Armed, in part, with the initial data from Richters

tions. Likewise, an increase in insulin-stimulated Akt

Fig. 1. Potential mechanisms by which prior exercise

J Appl Physiol VOL

rat skeletal muscle by Edward Hortons group at the

formation about the distal signals by which insulin and

A major advance in understanding at a molecular

was evident within seconds and that after 5 min of

Effect of exercise on cells other than those in skeletal

6. Burn JH and Dale HH. On the location of the action of insulin.

43. Pessin JE and Saltiel AR. Signaling pathways in insulin

J Appl Physiol VOL

61. Zierath JR, Krook A, and Wallberg-Henriksson H. Insulin

J Appl Physiol 93: 773781, 2002;

People with non-insulin-dependent Type 2 diabetes

43). Insulin sensitivity has been shown to be related to

8750-7587/02 $5.00 Copyright 2002 the American Physiological Society

Fig. 1. Exercise training-induced changes

correlated with improved insulin action on glucose

Insulin receptor substrates. Insulin signaling is a

molecules are likely to play complementary roles in the

Immediately after an acute bout of exercise, glucose

training-induced effects on IRSs have been elucidated.

tyrosine-phosphorylated molecule transmitting this

homeostasis associated with Type 2 diabetes and obesity

that regulate gene expression in skeletal muscle after

expressions, as well as in vitro MEF2 sequence-specific

glucose uptake and metabolism in tetraplegic persons: molecular

insulin receptor substrate family. J Biol Chem 272: 21403

J Appl Physiol VOL

and mitogenic signaling pathways in human skeletal muscle.

J Appl Physiol 93: 782787, 2002;

GLUCOSE TRANSPORT INTO SKELETAL muscle is primarily

Address for reprint requests and other correspondence: G. L.

8750-7587/02 $5.00 Copyright 2002 the American Physiological Society

the adaptation to exercise, because endurance training

To understand the mechanisms that increase muscle

pression may be regulated at both the transcriptional

promoter in muscle during exercise. A single bout of

To understand regulation of GLUT-4 expression, we

ingly, the greatest increase was found in white muscle

GLUT-4 expression in human skeletal muscle. Am J Physiol

J Appl Physiol VOL

J Appl Physiol 93: 788796, 2002;

8750-7587/02 $5.00 Copyright 2002 the American Physiological Society

glucose transport system in insulin-resistant states,

these insulin-independent mechanisms (see Refs. 43,

REGULATION OF SKELETAL MUSCLE

DEVELOPMENTAL ASPECTS OF INSULIN RESISTANCE

Skeletal muscle, which makes up 40% of the body

table PI3-kinase activity is detected in muscle from

It is well established that acute physical activity and