Annu. Rev. Med. 1998.

49:235–61
Copyright © 1998 by Annual Reviews Inc. All rights reserved

EXERCISE, GLUCOSE TRANSPORT,

AND INSULIN SENSITIVITY
Laurie J. Goodyear, PhD
Annu. Rev. Med. 1998.49:235-261. Downloaded from www.annualreviews.org

Research Division, Joslin Diabetes Center, Brigham and Women’s Hospital, and
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Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215;

e-mail: GOODYEAL@JOSLAB.HARVARD.EDU

Barbara B. Kahn, MD
Diabetes Unit, Division of Endocrinology and Metabolism, Beth Israel Deaconess
Medical Center, and Department of Medicine, Harvard Medical School, Boston,
Massachusetts 02215; e-mail: BKAHN@BIDMC.HARVARD.EDU

KEY WORDS: skeletal muscle, GLUT4, diabetes, insulin resistance, physical training

ABSTRACT
Physical exercise can be an important adjunct in the treatment of both
non–insulin-dependent diabetes mellitus and insulin-dependent diabetes
mellitus. Over the past several years, considerable progress has been made in
understanding the molecular basis for these clinically important effects of
physical exercise. Similarly to insulin, a single bout of exercise increases the
rate of glucose uptake into the contracting skeletal muscles, a process that is
regulated by the translocation of GLUT4 glucose transporters to the plasma
membrane and transverse tubules. Exercise and insulin utilize different sig-
naling pathways, both of which lead to the activation of glucose transport,
which perhaps explains why humans with insulin resistance can increase
muscle glucose transport in response to an acute bout of exercise. Exercise
training in humans results in numerous beneficial adaptations in skeletal
muscles, including an increase in GLUT4 expression. The increase in muscle
GLUT4 in trained individuals contributes to an increase in the responsive-
ness of muscle glucose uptake to insulin, although not all studies show that
exercise training in patients with diabetes improves overall glucose control.
However, there is now extensive epidemiological evidence demonstrating
that long-term regular physical exercise can significantly reduce the risk of
developing non–insulin-dependent diabetes mellitus.

235
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 236 GOODYEAR & KAHN

INTRODUCTION

It has long been recognized that physical exercise has important benefits for
people with diabetes (1). In the context of overall glucose homeostasis, a sin-
gle bout of exercise can markedly increase rates of whole-body glucose dis-
posal (2, 3) and increase the sensitivity of skeletal muscle glucose uptake to in-
sulin (4). These effects can last for several hours after the exercise ends (5–7).
Both the acute and persistent effects of exercise on glucose uptake and dis-
posal have important implications for individuals with diabetes in terms of
chronic metabolic control and acute regulation of glucose homeostasis. In ad-
Annu. Rev. Med. 1998.49:235-261. Downloaded from www.annualreviews.org

dition to the metabolic effects of a single exercise session, recent epidemiol-

ogical studies have determined that regular physical exercise can reduce the
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risk of developing non–insulin-dependent diabetes (NIDDM) (8–10). In the

first part of this chapter we review studies that have focused on elucidating the
cellular basis for the changes in glucose uptake and insulin sensitivity that oc-
cur in skeletal muscle in response to a single exercise session. The second part
of this chapter discusses investigations of the underlying molecular mecha-
nisms for the adaptations that occur in response to chronic physical training,
and the implications of these studies for people with diabetes.

EXERCISE INCREASES MUSCLE GLUCOSE UPTAKE

AND INSULIN SENSITIVITY

In the exercising muscle, the increased need for metabolic fuel is met partially
through an increase in the uptake and utilization of glucose. The first evidence
for this phenomenon was provided over a century ago, when chewing by horse
masseter muscle was shown to decrease the glucose concentration in the ve-
nous outflow from the muscle (11). In the 1950s, studies of rats (12) and per-
fused dog hindlimbs (13) confirmed this finding, and in the 1960s glucose up-
take kinetics were first described using incubated frog sartorius muscles con-
tracted in vitro (14, 15). Since these early studies, a considerable amount of
work has characterized the effects of exercise on glucose uptake in skeletal
muscle, and a few recent reviews have focused on this topic (16–18). In addi-
tion to the acute effects of exercise to increase muscle glucose uptake, the peri-
od after exercise is characterized by the muscle being more sensitive to the ac-
tions of insulin. This was first demonstrated in perfused rat hindlimb muscles
(19, 20) and was subsequently shown in studies of human subjects (3, 4, 6, 7).
One-legged exercise models in humans have demonstrated that the exercise-
induced increase in insulin sensitivity for glucose uptake is a local phenome-
non restricted to the exercised muscles (4, 21).
 EXERCISE AND GLUCOSE TRANSPORT 237

MECHANISMS FOR THE INCREASES IN GLUCOSE

UPTAKE AND INSULIN SENSITIVITY WITH ACUTE
EXERCISE
Numerous factors determine the rate of glucose uptake during and after exer-
cise. During exercise, one of the most important regulatory responses is an in-
crease in blood flow to the contracting skeletal muscles (reviewed in 16). The
increase in blood flow provides ample substrate to the working muscles, and
thus, glucose availability is usually not the rate-limiting factor for glucose
utilization when exercise is performed under normal physiological conditions.
Instead, glucose transport is thought to be the rate-limiting step in glucose
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utilization during exercise. Over the past several years considerable progress
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has been made in understanding the molecular basis for the effects of exercise
to increase glucose transport in skeletal muscle.

The Glucose Transport System

Glucose transport in skeletal muscle occurs primarily by facilitated diffusion,
utilizing glucose transporter carrier proteins. In mammalian tissues, glucose
transporters are a family of structurally related proteins that are expressed in a
tissue-specific manner (22). GLUT4 is the major isoform present in mouse,
rat, and human skeletal muscle, whereas the GLUT1 and GLUT5 isoforms are
expressed at a much lower abundance (23, 24). GLUT5 is a high-affinity fruc-
tose transporter with a much lower capacity to transport glucose (25). Exercise
and insulin are major mediators of glucose transport activity in muscle, which
occurs through an increase in the maximal velocity of transport (Vmax) without
an appreciable change in the substrate concentration at which glucose trans-
port is half maximal (K1/2)(14, 26–28).
Glucose Transporter Translocation
There is substantial evidence that a major mechanism by which exercise in-
creases glucose uptake in skeletal muscle is through the translocation of glu-
cose transporter proteins from an intracellular compartment to the surface of
the cell (29–38). In addition, sciatic nerve stimulation resulting in contraction
of hindlimb skeletal muscles in situ also increases the plasma membrane glu-
cose transporter number in the rat (39–42). The exercise-induced translocation
of glucose transporters is due to an increase in the plasma membrane content of
the GLUT4 isoform, since a single bout of exercise does not alter the abun-
dance of plasma membrane GLUT1 (33, 35, 36) or GLUT5 (EA Richter & HS
Hundal, personal communication). A recent study has demonstrated that a sig-
nificant percentage of the GLUT4 that is translocated to the plasma membrane
fraction with exercise associates with nonjunctional transverse tubules (38).
 238 GOODYEAR & KAHN

Although most of the work done in this area comes from studies using subcel-
lular fractionation of skeletal muscle, more recent studies using immunocyto-
chemical analysis of skeletal muscle sections by electron microscopy (43), or
labeling of cell surface GLUT4 protein using a membrane-impermeable bis-
mannose photolabel (44, 45), have confirmed that muscle contractions in-
crease plasma membrane GLUT4 protein.
Similar to the effects of exercise, insulin also causes GLUT4 translocation
in skeletal muscle (33, 36, 39, 46). Since blood flow is increased during exer-
cise, it is conceivable that the exercise-induced recruitment of GLUT4 to the
plasma membrane is due to increased delivery of insulin to the working mus-
Annu. Rev. Med. 1998.49:235-261. Downloaded from www.annualreviews.org

cles. However, when hindlimb skeletal muscles are contracted in situ in the ab-
sence of insulin, plasma membrane GLUT4 is increased to a similar degree to
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that which occurs with exercise in vivo (39–42). These findings demonstrate
that contraction can recruit GLUT4 to the plasma membrane in rat skeletal
muscle independent of insulin, and they provide a mechanism for earlier re-
ports showing that insulin is not required for muscle contraction to increase
glucose uptake in skeletal muscle (47–49).
The combination of exercise and insulin can have additive or partially addi-
tive effects on glucose transport (27, 50–52), which may be associated with an
additive effect on GLUT4 recruitment to the plasma membrane (42, 45). These
findings support the hypothesis that different mechanisms lead to the stimula-
tion of muscle glucose transport by exercise and insulin. In fact, there is evi-
dence that there are two distinct intracellular locations or pools of glucose
transporters in skeletal muscle, one that responds to exercise and one that re-
sponds to insulin (30, 33, 34). In these reports, insulin, but not exercise, was
shown to decrease glucose transporters from an intracellular microsomal
membrane fraction. Recently, modification of one of these fractionation pro-
cedures resulted in the isolation of a novel intracellular membrane fraction that
is sensitive to exercise (38, 53), giving further support to the hypothesis that
there are separate pools of glucose transporters in skeletal muscle. While there
are different sedimentation coefficients for the insulin- and exercise-sensitive
fractions, there appears to be little difference in the major protein composition
of these fractions (53). The exact intracellular locations of the putative exer-
cise- and insulin-stimulated GLUT4 pools have not yet been elucidated.
The majority of intracellular GLUT4 is located in small tubulo-vesicular
organelles (43, 46), and it is still not clear if these vesicles are unique intracel-
lular compartments or ubiquitously expressed organelles that are enriched in
GLUT4. As has recently been reviewed in detail (54), studies of adipose cells
suggest that there is a low rate of continuous recycling of GLUT4 in the basal
state, and that insulin acts primarily through increasing transporter exocytosis.
In skeletal muscle, it is not known if the exercise-induced recruitment of
 EXERCISE AND GLUCOSE TRANSPORT 239

GLUT4 occurs through the regulation of vesicular exocytosis. However, sev-

eral proteins that are involved in regulated endocytosis or exocytosis in other
tissues have also been identified as components of GLUT4-containing vesicles
in skeletal muscle (37, 53, 55–57). Of these proteins, the aminopeptidase
gp160/vp165 (53) and vesicle-associated membrane protein-2 (VAMP-2) (55)
translocate to the plasma membrane in response to physical exercise in skeletal
muscle, similar to the effects of insulin. In contrast, insulin, but not exercise,
results in the redistribution of Rab4 (37), a small GTP-binding protein that has
also been implicated in the regulation of GLUT4 translocation in adipose cells
(58, 59). The studies of Rab4 suggest that there may be distinct exercise- and
insulin-stimulated GLUT4-containing vesicles that utilize different molecular
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switches for mobilization.

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Intracellular Signaling Mechanisms

The molecular signaling pathways that lead to the stimulation of glucose uptake
in skeletal muscle or other cell types have not been completely elucidated. Un-
til recently, it was not known whether the analogous effects of insulin and ex-
ercise on skeletal muscle glucose uptake occur via similar or different molecu-
lar signals. For insulin action, the cascade of signaling events is initiated by in-
sulin binding to the extracellular α-subunit of the insulin receptor, autophos-
phorylation of tyrosine residues in the receptor β-subunit, tyrosine phosphory-
lation of the insulin receptor substrates IRS-1 and IRS-2, and activation of
phosphatidylinositol 3-kinase (PI 3-kinase) (reviewed in 60, 61). As for exer-
cise, several studies have clearly demonstrated that these proximal insulin-
signaling steps are not components of the signaling mechanism by which exer-
cise stimulates glucose uptake, since contractile activity does not stimulate
autophosphorylation of isolated insulin receptors (62), receptor and IRS tyro-
sine phosphorylation (63, 64), or PI 3-kinase activity (63, 64). Furthermore,
wortmannin, a PI 3-kinase inhibitor, does not inhibit contraction-stimulated
glucose transport in vitro (45, 65, 66). These signaling studies demonstrate that
the underlying molecular mechanisms leading to the insulin- and exercise-
induced stimulation of glucose uptake in skeletal muscle are distinct. In addi-
tion to these studies of muscle signaling intermediaries, we recently demon-
strated that the mitogen-activated protein kinase signaling cascade, which is
also increased in response to exercise (67, 68), is not involved in stimulating
glucose uptake with exercise (69). These findings have important implications
for determining the mechanisms by which insulin and exercise regulate skele-
tal muscle glucose uptake in human subjects. More importantly, in diabetic in-
dividuals who are insulin resistant, it is likely that exercise can function to acti-
vate alternative mechanisms to improve skeletal muscle glucose uptake.
 240 GOODYEAR & KAHN

There are several lines of evidence to suggest that the increase in intracel-
lular calcium that leads to the interaction of actin and myosin filaments
with muscle contraction is a critical mediator of contraction-stimulated glu-
cose transport (70). For example, the incremental increase in contraction-
stimulated transport correlates with the frequency of contraction, not the
amount of work or tension developed (14). In addition, caffeine, an agent that
causes contraction by increasing calcium release from the sarcoplasmic re-
ticulum in the absence of membrane depolarization, increases glucose
transport (15). Since cytoplasmic calcium concentrations are elevated for only
a fraction of a second following each muscle contraction, these molecules
probably do not directly activate the glucose transport system. Instead, the
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rise in cytosolic calcium may initiate or facilitate the activation of intracellu-

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lar signaling molecules or cascades of signaling proteins that lead to both the
immediate and prolonged effects of exercise on muscle glucose transport.
Protein kinase C (PKC) is an example of a calcium-dependent signaling in-
termediary that has been shown to be activated by muscle contraction (71,
72) and may be involved in the regulation of contraction-stimulated glucose
transport. Down-regulation of PKC by long-term phorbol ester treatment (72)
and inhibition of PKC using polymyxin B (73, 74) have both been associated
with decreases in contraction-stimulated glucose transport. There is also evi-
dence for an autocrine or paracrine component for the activation of con-
traction-stimulated glucose uptake, one important example being nitric ox-
ide. Nitric oxide is released from skeletal muscle contracted in vitro, and in-
hibition of nitric oxide synthase has been demonstrated to decrease both ba-
sal (75) and contraction-stimulated (76) glucose transport, an effect that may
be regulated by a cGMP-mediated mechanism (77, 78). Another molecule
that may be involved with contraction-stimulated glucose transport is kallik-
rein, which catalyzes the production of bradykinin and is a potential stimu-
lator of nitric oxide synthase. Adenosine has also been shown to be secreted
from contracting muscle fibers (79), and it has been suggested that the
adenosine receptor mediates the signaling mechanism through which con-
traction results in the synergistic stimulation of glucose transport (80). In
addition to the activation of specific intracellular signaling molecules, the
glycogenolytic process may be an important regulator of exercise-induced
GLUT4 translocation in skeletal muscle. Although there is still no direct evi-
dence, it has long been hypothesized that transporter molecules are associ-
ated with glycogen particles in the muscle, and that the contraction-
stimulated hydrolysis of glycogen releases GLUT4, leading to translocation
of these transporters to the cell surface. The effects of exercise and insulin
on GLUT4 translocation in skeletal muscle are illustrated schematically in
Figure 1.
 Annu. Rev. Med. 1998.49:235-261. Downloaded from www.annualreviews.org
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Figure 1 GLUT4 translocation in skeletal muscle. Muscle contractions and insulin cause the translocation of the GLUT4 glucose transporter pro-
teins to the plasma membrane and transverse tubules. GLUT1 and GLUT5 are present in the plasma membrane. The subcellular origin of the GLUT4-
containing vesicles is not clear, but exercise and insulin appear to recruit distinct GLUT4-containing vesicles, and/or mobilize different pools of
GLUT4 proteins. Insulin-stimulated GLUT4 translocation involves IRS-1 and PI 3-kinase, and the redistribution of Rab4. Contraction utilizes a PI 3-
EXERCISE AND GLUCOSE TRANSPORT

kinase and MAP kinase-independent mechanism and does not result in the redistribution of Rab4. The contraction signal is probably initiated by the
release of calcium from the sarcoplasmic reticulum and may involve an autocrine/paracrine mechanism (e.g. nitric oxide, adenosine, bradykinin),
241

protein kinase C (not shown), or a combination of these and other currently unknown factors. NO, Nitric oxide; PI, phosphatidylinositol.
 242 GOODYEAR & KAHN

Mechanisms for the Post-Exercise Increases in Insulin

Sensitivity
The period following exercise is typically characterized by elevated rates of
basal and insulin-stimulated glucose uptake. In fact, the increase in insulin-
stimulated glucose uptake that occurs in response to both exercise in vivo and
electrical stimulation to produce muscle contractions in situ can persist for
several hours following the cessation of exercise (19, 20, 50, 81–83). The mo-
lecular basis for this phenomenon has not been completely elucidated but ap-
pears to be dependent on multiple factors, including muscle glycogen concen-
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trations, humoral factors, and autocrine/paracrine mechanisms.

The degree of glycogen depletion resulting from the antecedent exercise
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session is clearly an important factor in determining the rate and duration of

the increase in muscle glucose uptake after exercise. The reversal of the in-
crease in glucose uptake and insulin sensitivity can be manipulated by muscle
glycogen concentrations, as carbohydrate feeding that results in increased gly-
cogen concentrations accelerates the return of basal rates of glucose uptake,
and carbohydrate restriction that maintains glycogen depletion slows this re-
versal process (82, 84). However, the level of glycogen is clearly not the only
regulator of glucose uptake post-exercise. Studies in isolated epitrochlearis
muscles (51, 83, 85) and individual tissues from perfused hindquarter muscle
(86) have shown that the reversal of glucose transport following contraction is
not always dependent on glycogen synthesis. In these experiments, glycogen
concentrations were maintained at a low level (depleted); however, in all stud-
ies, 3-O-methylglucose transport returned to baseline or near baseline values.
The cellular mechanism leading to the increase in insulin sensitivity after
exercise has been hypothesized to involve enhanced insulin signaling. How-
ever, exercise does not change insulin binding to its receptor (62, 87, 88), and
prior exercise does not increase insulin-stimulated receptor tyrosine kinase ac-
tivity in skeletal muscles obtained from rats (62) or humans (JFP Wojtasewski
& E Richter, unpublished observation). Furthermore, prior contraction of rat
hindlimb skeletal muscles has been shown to actually cause a paradoxical de-
crease in insulin-stimulated tyrosine phosphorylation of IRS1 and IRS1-
associated PI 3-kinase activity (67). Consistent with these finding are recent
studies showing that insulin’s ability to activate IRS1-associated PI 3-kinase
activity in vivo is diminished in previously exercised human muscle (JFP
Wojtasewski & E Richter, unpublished observation). These studies rule out a
role for enhanced insulin signaling as a mechanism for increased glucose up-
take after exercise and provide additional support to the hypothesis that exer-
cise and insulin act through distinct signaling mechanisms. The lack of en-
hancement of these steps in the insulin signaling cascade may not be surpris-
 EXERCISE AND GLUCOSE TRANSPORT 243

ing, since increased sensitivity following exercise is not limited to insulin. The
effect of hypoxia on glucose transport is also markedly amplified in muscles
studied 3 h after exercise (89), and hypoxia has also been shown to use a sig-
naling pathway that bypasses the insulin receptor, IRS-1 and IRS-2, and the
activation of PI 3-kinase (90).
Some studies suggest that the persistent increase in glucose uptake post-
exercise requires the presence of insulin (51, 83). In isolated epitrochlearis
muscles in vitro, there was a persistent increase in glucose uptake only in mus-
cles that were incubated with insulin following exercise (51, 83). These inves-
tigators hypothesized that exercise causes a recruitment of glucose transport-
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ers to the plasma membrane and that the presence of insulin will slow internali-
zation of glucose transporters to the intracellular pool, thus keeping transport
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elevated. The finding that rates of glucose uptake in hindquarter skeletal mus-
cle are elevated for several hours after exercise in the presence but not the ab-
sence of insulin supports this hypothesis (50). More recently it was shown that
when intact muscles are isolated, washed, and contracted in vitro, there is no
increase in insulin sensitivity after contractions (89). This work, and a subse-
quent report, suggest that a serum factor, probably a protein, is required for the
effects of contraction to enhance insulin sensitivity (91). In contrast to these
findings are the results from another study indicating that adenosine receptors
may mediate the ability of muscle contraction to increase insulin-stimulated
glucose uptake (80). Taken together, these studies suggest that there may be no
single factor that regulates the enhanced muscle insulin sensitivity for glucose
uptake in the post-exercise state. Instead, this physiological phenomenon may
be regulated by a combination of serum factors, autocrine/paracrine mecha-
nisms, and muscle glycogen concentrations.

EXERCISE AND GLUCOSE TRANSPORT IN INSULIN-

RESISTANT STATES
The effects of exercise on glucose uptake have been studied in a number of ro-
dent and human models of insulin resistance. Whereas in most insulin-resistant
states, such as obesity and NIDDM, GLUT4 gene expression is reduced in adi-
pose cells, in skeletal muscle GLUT4 expression is normal (92–94). Thus, the
decreased glucose uptake in response to insulin (insulin resistance) in skeletal
muscle results from alterations in the translocation, docking, or fusion of glucose
transporters at the plasma membrane or T tubules, or potentially from changes
in the specific activity of the transporters (moles of glucose transported/trans-
porter/unit of time). Such defects are thought to result from impaired intracel-
lular signaling, and in some states this may involve defective activation of PI
3-kinase, which results, at least in part, from decreased expression of the p85
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244
GOODYEAR & KAHN
 EXERCISE AND GLUCOSE TRANSPORT 245

regulatory subunit of PI 3-kinase. Insulin-stimulated activation of PI 3-kinase

is impaired in skeletal muscle in rodent models of genetic obesity and hyper-
insulinemic diabetes (95, 96), in rats rendered insulin resistant with high-fat
feeding (97) or glucocorticoid treatment (98), and in humans with obesity (99)
and NIDDM (100). However, as described above, the activation of PI 3-kinase
is not important for the effects of exercise to stimulate glucose transport.
In many insulin-resistant states, the stimulation of glucose transport and
GLUT4 translocation in response to exercise is normal. For example, in skele-
tal muscle from the genetically obese Zucker rats, insulin-stimulated glucose
transport is markedly decreased in spite of normal GLUT4 expression (101,
102). Studies performing subcellular fractionation of muscle followed by
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immunoblotting for GLUT4 indicate that the defect is in the insulin-stimulated

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translocation/fusion of GLUT4 with the plasma membrane (103). In contrast,

exercise (104, 105) and contraction (106) increase glucose uptake and GLUT4
translocation normally in muscle from these same rats (Figure 2). Other states
of insulin resistance such as short periods of high-fat feeding or immobiliza-
tion are also associated with insulin resistance in skeletal muscle in spite of
normal GLUT4 expression (107, 108). The glucose transport response to exer-
cise is normal in these states also (107, 108). With longer periods of high-fat
feeding (109) or immobilization (110, 111), GLUT4 expression in muscle is
reduced and once GLUT4 is down-regulated, exercise-stimulated glucose
transport becomes impaired.
In humans with obesity or NIDDM, defects in insulin signaling are thought
to be involved in the etiology of insulin resistance. Muscles from these sub-
jects increase glucose transport normally in response to a variety of stimuli that
act downstream of the insulin receptor, such as hypoxia, okadaic acid, vana-
date, and phenylarsine oxide (90). These results suggest that the GLUT4 trans-
location/ fusion machinery is operational but that defects specifically in the in-
sulin signaling pathway cause resistance to insulin. The effects of contraction
or exercise on glucose transporter translocation in muscles from NIDDM sub-
jects have not been studied. However, in vivo studies in obese, NIDDM sub-
jects show a normal increase in whole-body glucose utilization during moder-
ate exercise (112). In nonobese NIDDM subjects, exercise-induced leg glu-
cose uptake was actually increased compared with nondiabetic control sub-

Figure 2 Effects of insulin and exercise on plasma membrane glucose transporters in lean and
obese Zucker rats. (Top) Plasma membranes were partially purified from hindlimb skeletal mus-
cle, and glucose transporter number (R0) was determined by Scatchard analysis derived from D-
glucose inhibitable cytochalasin B binding. Values are means ± SE; n = 5–10/group. (Adapted
from References 103, 104.) (Bottom) Schematic illustration showing that exercise, but not insu-
lin, is effective in causing glucose transporter translocation in the obese Zucker rat.
 246 GOODYEAR & KAHN

jects (113). It was postulated that the latter finding resulted from a
hyperglycemia-induced increase in the mass action of glucose, since the glu-
cose clearance rate that takes into account the ambient glucose concentration
was comparable in the two groups. The lack of impairment in the response of
subjects with obesity and diabetes to exercise in spite of marked insulin resis-
tance underscores the fact that exercise and insulin utilize different signaling
pathways to stimulate glucose uptake. These sorts of observations underlie the
utility of exercise in the prevention and treatment of NIDDM. A better under-
standing of the signaling pathway(s) utilized by exercise could lead to new
therapeutic approaches to prevent or treat NIDDM.
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EPIDEMIOLOGIC STUDIES INDICATING

BENEFICIAL EFFECTS OF EXERCISE IN
THE PREVENTION OF NIDDM
Exercise training, defined as repeated bouts of exercise, results in multiple
physical and metabolic changes, including a significant increase in aerobic ca-
pacity. The metabolic changes have important implications for individuals
who have impaired glucose tolerance (IGT), gestational diabetes, and
NIDDM. Epidemiological studies show that physical inactivity may be a risk
factor for NIDDM, at least in some ethnic groups, especially among Mexican
Americans (reviewed in 114). In persons without diabetes, glucose and insulin
levels after a meal are significantly higher in less-active compared with more-
active persons (114). Although cross-sectional studies do not find a consistent
association between physical activity and NIDDM in all populations, such an
association has been shown in both case-control and cohort studies (114)
(Table 1). One population-based study of women aged 55–69 showed that
high levels of physical activity reduced the risk of developing NIDDM by
50% compared with age-matched women with low levels of physical activity
(115).
Prospective cohort studies of male college alumni (10), female nurses (8),
and male physicians (9) demonstrate a reduced risk of developing NIDDM
with increased physical activity. This is particularly evident among high-risk
persons, defined as those with a high body mass index, high blood pressure, or
a parent with NIDDM (10). In one study, each 500 kcal of additional leisure-
time physical activity per week was associated with a 6% decrease in the risk
of developing NIDDM. Subjects participating in these prospective studies
ranged from 34–84 years old (see Table 1). In addition, in feasibility studies in
Sweden and China, physical activity has been instituted as part of an interven-
tion to prevent the development of diabetes among persons with impaired glu-
 EXERCISE AND GLUCOSE TRANSPORT 247

Table 1 Epidemiological studies demonstrating the efficacy of physical activity in the

prevention of NIDDMa
Study population Main findings Dose response Reference
Case control study
Women, aged 55-69 High levels of physical activity de- Yes 115
creased risk of NIDDM by 50%.
Cohort studies
Male college alums, Physical activity level was inversely Yes 10
aged <45–55 related to risk of developing
NIDDM, especially in men at high
risk for NIDDM. 6% decrease in
risk of NIDDM for each 500 kcal
Annu. Rev. Med. 1998.49:235-261. Downloaded from www.annualreviews.org

increment in physical activity.

Female registered Women who engaged in vigorous No 8
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nurses, aged 34–59 physical activity at least once per

week had a 16% lower adjusted
relative risk of NIDDM during an
8-year follow up compared with
women with no vigorous physical
activity.
Male physicians, Men who engaged in vigorous physi- Yes 9
aged 40–84 cal activity at least once per week
had a 29% lower adjusted relative
risk of NIDDM during a 5-year
follow-up compared with men
with no vigorous physical activity.
Feasibility studiesb
Men with impaired Half as many men who exercised NA 116
glucose tolerance, regularly developed NIDDM at 5
aged 47–49 years of follow-up compared with
men with IGT who did not exer-
cise regularly. OGTT normalized
in 50% who exercised regularly.
Men and women with 8.3 cases of NIDDM per 100 person Yes 117
impaired glucose years in subjects who exercised
tolerance, aged regularly compared with 15.7 cases
25–74 per 100 person years in the control
group at 6 years of follow-up.
a
NIDDM, Non–insulin-dependent diabetes mellitus; OGTT, oral glucose tolerance test; NA,
not available.
b
Prospective assessment of efficacy of a regular exercise program to prevent NIDDM in sub-
jects with impaired glucose tolerance (IGT).

cose tolerance (116, 117). Both studies showed an ∼50% reduction in the
number of subjects who developed diabetes over a five- to six-year follow-up
in the group that exercised compared with the group that did not. All of these
approaches indicate a significant beneficial effect of regular physical exercise
to prevent NIDDM among high-risk subjects.
 248 GOODYEAR & KAHN

PHYSIOLOGIC MECHANISMS FOR THE BENEFICIAL

EFFECTS OF EXERCISE TRAINING ON INSULIN ACTION
IN MUSCLE
Multiple studies have addressed the physiological and molecular mechanisms
underlying these beneficial effects of exercise (reviewed in 114). In 1972
Bjorntorp et al (118) first suggested that exercise training may increase tissue
sensitivity to insulin. This investigation, along with several subsequent studies
(119–123), demonstrated that trained individuals have a smaller increase in
plasma insulin concentrations in response to a glucose load than do sedentary
people and, in spite of the lower insulin response, have an unchanged or im-
Annu. Rev. Med. 1998.49:235-261. Downloaded from www.annualreviews.org

proved glucose tolerance. Additional studies using the hyperinsulinemic-

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euglycemic clamp demonstrated that exercise-trained people have a higher

rate of insulin-stimulated glucose disposal than do their sedentary counterparts
(124–128). Although these results have been interpreted to indicate that exer-
cise training results in an increase in tissue sensitivity to insulin, this concept
has been complicated by the fact that, as discussed in previous sections, an
acute bout of exercise produces major effects on both whole-body glucose dis-
posal and metabolism (2, 3, 5–7, 129) and skeletal muscle glucose uptake and
metabolism (4, 14, 19, 81, 130) that can last for several hours after the last ex-
ercise session. Hence, many of the effects of regular exercise may be due to the
overlapping effects of individual exercise sessions and not to long-term adap-
tations to exercise training.
Several studies have attempted to discriminate between long-term adapta-
tions in insulin sensitivity in exercise-trained individuals and the effect of a
previous training bout (126, 129, 131–134). Heath et al (132) showed that the
plasma insulin response to an oral glucose load is increased twofold in well-
trained subjects after 10 days without exercise compared to when the same
subjects were exercising regularly. This level of insulin response in the trained
subjects after 10 days of inactivity was similar to that of untrained subjects
(132). However, this study also demonstrated that the performance of a single
exercise bout by the trained subjects on day 11 of the protocol did not com-
pletely return the insulin response to the trained level, suggesting that training
results in a slightly greater blunting of the insulin response to a glucose load
than does a single exercise bout (132). Using the hyperinsulinemic clamp pro-
cedure, King et al (134) also concluded that the effects of exercise training in
increasing insulin action are transient. Additional studies using the euglycemic
clamp procedure (at submaximal insulin concentrations) demonstrated that
elevated insulin-stimulated glucose disposal rates, and therefore the improved
insulin sensitivity, in trained individuals disappear after 7 (131) and 10 days
(133) of inactivity. On the other hand, maximal insulin-stimulated glucose dis-
 EXERCISE AND GLUCOSE TRANSPORT 249

posal was unaffected by 10 days of inactivity (133), suggesting that the reduc-
tion in insulin action following short-term inactivity is the result of a decrease
in insulin sensitivity and not a decrease in insulin responsiveness. Similarly,
after comparing trained subjects with untrained subjects who had undergone
an acute bout of exercise (129), and after comparing trained subjects before
and after five days of detraining (126), a different group of investigators con-
cluded that an increase in maximal insulin action on whole-body glucose up-
take (insulin responsiveness) but not insulin sensitivity is a long-term adapta-
tion caused by endurance exercise training.
A recent study that found an increase in insulin action with exercise training
Annu. Rev. Med. 1998.49:235-261. Downloaded from www.annualreviews.org

investigated the mechanism using nuclear magnetic resonance spectroscopy in

offspring of diabetic parents (135). These subjects are insulin resistant and
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have an increased risk of developing NIDDM. Six weeks of exercise training

resulted in reversal of a defect in insulin-stimulated glucose transport/phos-
phorylation in muscle, which led to a twofold increase in insulin-stimulated
glycogen synthesis (135). These alterations may underlie the beneficial effect
of exercise to prevent NIDDM among high-risk people (see Table 1).
Some of the beneficial effects of exercise training on insulin action may be
indirect, resulting from weight loss or changes in body composition (increased
lean body mass). However, even studies that have controlled for these effects
detect an improvement in insulin sensitivity due to exercise (136, 137). Hence,
exercise appears to improve insulin action independent of changes in body
composition, and there may be additive effects of exercise and decreased adi-
posity.

MOLECULAR MECHANISMS FOR LONG-TERM

ADAPTATION TO EXERCISE TRAINING
Exercise training in rats results in increased mRNA levels for the insulin re-
ceptor, IRS-1, and MAP kinase (ERK1) (138). However, studies of insulin
binding (139–141) and insulin receptor tyrosine kinase activity (142) in skele-
tal muscle showed that functional alterations in these signaling molecules do
not occur in the trained state. In contrast, there is now substantial evidence in
animals (143–146) and humans (136, 147–149) that exercise training in-
creases the expression of GLUT4 in skeletal muscle. Expression of GLUT4 in
skeletal muscle is increased as a result of exercise training in normal rats, as
well as in insulin-resistant models such as the obese Zucker rat and old fat rats
[reviewed in (18)]. In contrast, expression of the GLUT1 glucose transporter
was not altered in muscle from trained rats (150). Transgenic mice expressing
a minigene of GLUT4 consisting of 7 kb of 5’ flanking and 1 kb of 3’ flanking
sequence, as well as all introns and exons of GLUT4, showed increased ex-
 250 GOODYEAR & KAHN

pression of both endogenous and transgenic GLUT4 in muscle after exercise

training (151). Hence, the exercise responsive cis-regulatory elements are lo-
cated within these regions of GLUT4.
Importantly, parallel effects of exercise training on GLUT4 expression are
seen in humans. Cross-sectional studies show that athletes have higher levels
of GLUT4 expression in skeletal muscle than age-matched nonathletic sub-
jects (152). Prospective studies show that exercise training increases skeletal
muscle GLUT4 protein by 80% in nondiabetic men (147) and by 60% in men
and women with IGT (136). Figure 3 shows results from the latter study, in
which previously sedentary subjects with IGT (mean age 64 ± 2 years) under-
Annu. Rev. Med. 1998.49:235-261. Downloaded from www.annualreviews.org

went exercise training at 50–75% heart rate reserve for 12 weeks. GLUT4 lev-
els increased in 9 of 12 subjects and the mean increase for the group was 60%
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(136). In another study, exercise training significantly increased skeletal mus-

cle GLUT4 protein by 23% in men with NIDDM and by 39% in nondiabetic
men (149). GLUT4 mRNA was also increased in muscle from both nondia-
betic men and men with NIDDM (149). Thus, exercise training increases mus-
cle GLUT4 gene expression at a pretranslational level in nondiabetic, insulin-
resistant, and frankly diabetic subjects. The enhanced expression of GLUT4 is
associated with modest increases in insulin-stimulated glucose disposal meas-
ured by euglycemic clamp (136), in insulin sensitivity measured by modified
intravenous glucose tolerance test (147), and in reduced glucose (136) and in-
sulin (148) excursion during a glucose tolerance test. However, it is not clear
that the changes in GLUT4 expression fully explain the increased insulin sen-
sitivity associated with exercise training. Interestingly, training cessation for
14 days in endurance-trained (runners) or strength-trained (weight lifters) sub-
jects was associated with a decrement in insulin sensitivity but no reduction in
GLUT4 expression in muscle (153), suggesting that multiple factors are in-
volved in the changes in insulin sensitivity with detraining.

A ROLE FOR EXERCISE IN THE TREATMENT OF IDDM,

NIDDM, AND GESTATIONAL DIABETES
The therapeutic effects of exercise in the treatment of diabetes have been rec-
ognized since the preinsulin era. As early as 1919 there were reports of exer-
cise lowering blood glucose concentrations in diabetic patients and acutely, al-
beit temporarily, improving glucose tolerance (154). In 1926, shortly after the
discovery of insulin, exercise was shown to potentiate the hypoglycemic effect
of insulin (155). Subsequently, regular physical activity was shown to lead to
decreased insulin requirements and increased risk of hypoglycemic episodes
in insulin-treated diabetic people. In the 1935 edition of The Treatment of Dia-
betes Mellitus (1), exercise was recommended in the “everyday treatment of
 EXERCISE AND GLUCOSE TRANSPORT 251
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Figure 3 Exercise training increases GLUT4 protein levels in human skeletal muscle. (Top)
Western blot of GLUT4 protein in vastus lateralis muscle obtained by needle biopsy before train-
ing (− ) and after 12 weeks of training (+) in three representative subjects with impaired glucose
tolerance. Pre- and post-training samples (150 µg of muscle homogenate protein) from the same
subject are run on adjacent lanes. Mr, Relative molecular mass. (Bottom) Quantitation of GLUT4
protein levels in muscle samples from 12 subjects pre- and post-training. Western blots of
GLUT4 were quantitated by densitometric scanning. Open symbols denote the three subjects in
which GLUT4 levels did not increase. Solid symbols not connected by lines represent mean + SE
in all 12 subjects. Significant training effect for all subjects at p<0.02. Reprinted with permission
from (132).
 252 GOODYEAR & KAHN

diabetes.” Subsequently, it became evident that exercise may exacerbate hy-

perglycemia and promote ketosis in insulin-deficient diabetic people who are
in poor metabolic control (156). More recent studies of people with insulin-de-
pendent diabetes mellitus show that exercise training improves insulin sensi-
tivity (157, 158) but usually not glucose control (158, 159). The lack of im-
provement in glucose control may be due, in part, to increased caloric intake to
prevent hypoglycemia during and after exercise (159). Therefore, it might be
possible to develop treatment regimens to augment the beneficial effects of ex-
ercise on glucose control in IDDM. Exercise training has other beneficial ef-
fects, including improved cardiovascular fitness and blood lipid profiles,
which could potentially improve morbidity and mortality in people with
Annu. Rev. Med. 1998.49:235-261. Downloaded from www.annualreviews.org

IDDM as well as with NIDDM.

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In people with NIDDM, exercise has been shown to increase insulin-

stimulated glucose disposal (160). Postprandial exercise of moderate intensity
in untrained NIDDM subjects decreases glycemia and plasma insulin levels af-
ter a single meal, but this effect does not persist throughout the day (161). In
contrast, exercise training has a more prolonged effect on insulin sensitivity. In
one study in which obese, non–insulin-dependent diabetic and insulin-dep-
endent diabetic subjects were studied, Koivisto et al (157) demonstrated that
six weeks of exercise training increased insulin sensitivity by 25–35%. Inter-
estingly, even with these increases, the absolute rate of insulin-mediated glu-
cose metabolism was well below that of untrained, age-matched control sub-
jects (157).
An exercise program can be an important part of a treatment regimen for
NIDDM (162); a regular exercise program potentiated the effects of diet or sul-
fonylurea therapy to lower glucose levels and improve insulin sensitivity in
obese NIDDM subjects (163). In gestational diabetes also, some but not all
studies show a beneficial effect of exercise on glucose control (164, 165). In
obese adolescents, another high-risk group for developing NIDDM, a 15-week
program of supervised mild-intensity exercise resulted in decreased glucose
and insulin levels, as well as in decreased blood pressure and low-density-
lipoprotein cholesterol levels (166). Physical training also decreases the insu-
lin resistance of aging (167).
Multiple factors may modulate the response to exercise training in NIDDM
subjects, such as the degree of insulin resistance and insulin deficiency, the
frequency and intensity of exercise, the adherence to diet, weight loss, etc. In-
sulin sensitivity and the rate of glucose disposal are related to cardio-
respiratory fitness even in older persons (124). The additional potential benefi-
cial effects of exercise training to lower cardiovascular risk in NIDDM sub-
jects may reduce the risk of macrovascular or atherosclerotic complications of
diabetes (114). These beneficial effects include lowering blood pressure, im-
 EXERCISE AND GLUCOSE TRANSPORT 253

proving blood lipid profiles, promoting weight loss—especially reduction of

intraabdominal fat (a known risk factor for insulin resistance), and promoting a
sense of well-being (114, 168).

SUMMARY

There has been considerable progress over the past several years in under-
standing the molecular basis for the clinically important effects of exercise and
physical training on glucose uptake and insulin sensitivity in skeletal muscle.
We now know that the GLUT4 glucose transporter plays a major role in regu-
Annu. Rev. Med. 1998.49:235-261. Downloaded from www.annualreviews.org

lating glucose transport during exercise, and it is also clear that exercise and
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insulin utilize distinct signaling pathways that lead to the activation of glucose
transport in skeletal muscle. Thus, it is not surprising that studies in animals
and humans have shown that exercise can increase muscle glucose uptake, of-
ten in the face of moderately severe insulin resistance. Complete elucidation of
the molecules involved in signaling the exercise-induced activation of glucose
transport will be important, and these proteins are potential sites for future
pharmacologic intervention. Exercise training has been associated with in-
creases in insulin action in muscle, and there is some evidence that a program
of physical training can improve glucose control in individuals with NIDDM
and gestational diabetes. Furthermore, it is now known that long-term regular
physical exercise can significantly reduce the risk of developing NIDDM. Al-
though most research suggests that physical training in people with IDDM
does not improve glucose control, regular physical exercise can reduce insulin
requirements. In addition, there is overwhelming evidence that regular physi-
cal exercise can reduce the risk of developing cardiovascular disease, lipid ab-
normalities, and several other conditions that are known to be significant com-
plications associated with diabetes. Thus, physical exercise continues to be an
important adjunct to the treatment of all forms of diabetes.

ACKNOWLEDGMENTS
Work in our laboratories was supported by NIH grant AR-42238 and a grant
from the Juvenile Diabetes Foundation International (to LJ Goodyear), and by
NIH grant DK-43051, US Department of Agriculture grant #9400703, and
grants from the American Diabetes Association and the Juvenile Diabetes
Foundation International (to BB Kahn).

Note added in proof: After submission of this manuscript, the beneficial ef-
fects of physical activity in subjects with IDDM and NIDDM were reviewed
(Clark DO. 1997. Diab. Care 20:1176-82).
 254 GOODYEAR & KAHN
Visit the Annual Reviews home page at
http://www.AnnualReviews.org.
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