Adv Physiol Educ 38: 308–314, 2014;
Refresher Course
Exercise and type 2 diabetes: molecular mechanisms regulating glucose
uptake in skeletal muscle
Kristin I. Stanford and Laurie J. Goodyear
Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Department of Medicine, Brigham and Women’s
Hospital, Harvard Medical School, Boston, Massachusetts
Submitted 2 July 2014; accepted in final form 2 October 2014
Stanford KI, Goodyear LJ. Exercise and type 2 diabetes: molec-
ular mechanisms regulating glucose uptake in skeletal muscle. Adv
Physiol Educ 38: 308 –314, 2014; doi:10.1152/advan.00080.2014.—
Exercise is a well-established tool to prevent and combat type 2
diabetes. Exercise improves whole body metabolic health in people
with type 2 diabetes, and adaptations to skeletal muscle are essential
for this improvement. An acute bout of exercise increases skeletal
muscle glucose uptake, while chronic exercise training improves
mitochondrial function, increases mitochondrial biogenesis, and in-
creases the expression of glucose transporter proteins and numerous
metabolic genes. This review focuses on the molecular mechanisms
that mediate the effects of exercise to increase glucose uptake in
skeletal muscle.
exercise; type 2 diabetes
DIABETES IS A COMPLEX DISEASE that affects millions of people
worldwide. There are 23.6 million people in the United States
or ⬃8% of the population that have diabetes, a number that has
doubled over the last 15 yr and is continuing to increase at
epidemic rates (56). It is predicted that 1 in 3 adults in the
United States will have diabetes by 2050, yielding enormous
tolls at individual, public health, and economic levels (56).
Type 2 diabetes arises from a combination of genetic sus-
ceptibility and environmental factors including physical inac-
tivity and poor nutrition (25). Obesity plays a role in the
majority of cases of type 2 diabetes (7a). The progression of
obesity increases the risk for the development of type 2 diabetes;
as a person becomes more obese, they enter a more insulin-
resistant state, leading to impaired glucose tolerance, which can
potentially lead to the onset of type 2 diabetes. As the disease
progresses, the risk of complications, such as retinopathy, ne-
phropathy, and neuropathy, increases. In fact, type 2 diabetes is
the leading cause of blindness, kidney failure, and amputations
and a major cause of heart attacks and strokes (56).
In people with type 2 diabetes, insulin levels are normal or
high, but tissues such as liver, skeletal muscle, and adipose
tissue become resistant to insulin. The pancreas compensates
by producing large amounts of insulin, and this overproduction
of insulin can eventually fail. This increase in circulating
insulin can result in impaired glucose transport into liver,
skeletal muscle, and adipose tissue (11). While type 2 diabetes
is usually adult onset, the number of children and adolescents
afflicted by this disease is increasing, likely as a result of
increased rates of obesity and poor nutrition and an increas-
ingly sedentary lifestyle.
Address for reprint requests and other correspondence: K. I. Stanford,
Section on Integrative Physiology and Metabolism, Joslin Diabetes Center,
Dept. of Medicine, Brigham and Women’s Hospital, Harvard Medical School,
Boston, MA 02215 (e-mail: kristin.stanford@joslin.harvard.edu).
308 1043-4046/14 Copyright © 2014 The American Physiological Society
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doi:10.1152/advan.00080.2014.
Exercise Training Improves Metabolic Health in People
With Type 2 Diabetes
While rates of diabetes are on the rise, it has long been
recognized that exercise has important health benefits for
people with type 2 diabetes. One of the environmental factors
considered a risk for the development of insulin resistance and
type 2 diabetes is a lack of physical activity, and regular
physical exercise can delay or prevent the onset of this disease
(18, 58, 78).
Randomized trials have found that lifestyle interventions
including ⬃150 min/wk of physical activity, combined with
diet-induced weight loss, reduced the risk of type 2 diabetes by
58% in an at-risk population (58, 78). Interventions of exercise
alone have proved to be just as effective in terms of prevention
of the progression of type 2 diabetes as programs of diet alone
or diet and exercise combined (9). Exercise training in type 2
diabetic patients improves management of blood glucose lev-
els, body weight, lipids, blood pressure, cardiovascular disease,
mortality, and overall quality of life (13, 19, 38, 47, 48, 62, 82).
The more recent Look AHEAD study has shown that combined
weight loss and physical activity in people with type 2 diabetes
resulted in modest weight loss of ⬃6%, improved glycolated
hemoglobin, improved mobility, and improved kidney func-
tion, but no improvement in cardiovascular disease over a
10-yr period (13, 47, 48, 62). However, since the level of
fitness was only assessed through year 4 of the study, conclu-
sions on the effects of fitness level on cardiovascular disease
cannot be made (13, 47, 48, 62). Another recent study (23) has
shown that 6 mo of moderate-intensity exercise training de-
creased visceral fat mass and decreased hepatic triglyceride
content in people with type 2 diabetes and that this program of
exercise alone was more effective than programs of diet alone.
Another recent study (19) showed that increasing physical
activity in adults with type 2 diabetes resulted in partial or
complete remission of type 2 diabetes in 11.5% of subjects
within the first year of intervention and an additional 7% had
partial or complete remission of type 2 diabetes after 4 yr of
exercise intervention. Complete remission was defined by
glucose normalization without need for drugs, and partial
remission was defined as a transition to prediabetic or normal
glucose levels without drug treatment (19). Taken together,
these data demonstrate the beneficial effects of exercise train-
ing to combat type 2 diabetes.
One of the most well-established mechanisms through which
type 2 diabetics improve metabolic health with exercise is
through adaptations to skeletal muscle, which, in turn, de-
creases skeletal muscle insulin resistance. Here, we will dis-
cuss the effects of exercise on skeletal muscle, because skeletal
muscle is responsible for the majority of glucose uptake in the
 Refresher Course
MOLECULAR MECHANISMS REGULATING GLUCOSE UPTAKE IN MUSCLE 309

postprandial state (6, 11). In the following sections, we will
discuss specific adaptations of skeletal muscle to both acute
and exercise training on skeletal muscle glucose uptake and
metabolism.
Effects of Acute Exercise on Skeletal Muscle Glucose Uptake
It is well established that insulin is a potent simulator of
glucose transport in skeletal muscle. In people with type 2
diabetes, insulin-stimulated glucose uptake in skeletal muscle
is impaired. However, exercise-stimulated glucose uptake in
people with type 2 diabetes is normal or at near normal levels
(51). Because exercise-stimulated glucose uptake is normal in
people with type 2 diabetes, defining insulin-independent
mechanisms in the control of exercise-stimulated skeletal mus-
cle glucose uptake is of critical importance as a potential means
to treat diabetes. During the last several years, researchers have
learned much about the signaling mechanisms that regulate
exercise-induced glucose transport. There are many lines of
evidence that show that exercise activates molecular signals
that bypass defects in insulin action in skeletal muscle.
Both insulin and exercise increase skeletal muscle glucose
uptake by translocation of glucose transporter 4 (GLUT4), the
predominant GLUT in muscle, from an intracellular location to
the plasma membrane. Insulin and exercise stimulate GLUT4
translocation through distinct signaling mechanisms. Insulin
signaling involves rapid phosphorylation of the insulin recep-
tor, insulin receptor substrate-1/2 on tyrosine residues, and the
activation of phosphatidylinositol 3-kinase (14, 17). Exercise,
however, has no effect on insulin receptor and insulin receptor
substrate-1/2 tyrosine phosphorylation or on phosphatidylino-
sitol 3-kinase activity (17, 75). In fact, mice that lack insulin
receptors in skeletal muscle [muscle-specific insulin receptor
knockout (KO) mice] have normal exercise-stimulated glucose
uptake (85). These data clearly demonstrate that insulin and
exercise mediate GLUT4 translocation in skeletal muscle
through distinct proximal signaling mechanisms.
Acute exercise activates multiple signaling pathways, but
the activated signaling pathways necessary for increased glu-
cose uptake and GLUT4 translocation are not well understood.
Muscle contraction involves changes in energy status (i.e.,
increased AMP/ATP), increases in intracellular Ca2⫹ concen-
tration, increased ROS, and PKC. These changes activate
various signaling cascades, some of which likely work to
phosphorylate Tre-2/USP6, BUB2, cdc16 domain family
member 1 (TBC1D1) and Akt substrate of 160 kDa (AS160)
and activate GLUT4 translocation. Here, we will discuss some
of the various signaling cascades that have been implicated in
exercise-stimulated glucose uptake (Fig. 1) (63, 66).
AMP-Activated Protein Kinase
AMP-activated protein kinase (AMPK) and its primary up-
stream kinase, liver kinase B1 (LKB1), are the most widely
studied proteins implicated in skeletal muscle glucose transport
in response to exercise. AMPK is a heterotrimeric protein

Insulin Glucose
Exercise
Insulin
Receptor

P
P Rac1 Ca2+ AMP/ATP ROS Mechanical
P
P
P
LKB1
Rac1
P IRS-1 P p85- p110 PAK1
calmodulin NRG
PI 3-Kinase SNARK AMPK
aPKCs
CaMKs

PAK1
Akt GLUT4 Translocation

P PP P P P P PP P P P
RAB RAB
CBD GAP CBD GAP
domain domain

TBC1D1 AS160
Fig. 1. Exercise and insulin regulation of glucose transport. A proposed model for the signaling pathways mediating exercise- and insulin-induced skeletal muscle
glucose transport is shown. IRS-1, insulin receptor substrate-1; PAK, p21 protein (Cdc42/Rac)-activated kinase 1; LKB1, liver kinase B1; PI3K, phosphati-
dylinositol 3-kinase; CaMK, Ca2⫹/calmodulin-dependent protein kinase; SNARK, sucrose nonfermenting AMP-dependent protein kinase (AMPK)-related
kinase; NRG, neuroglian; aPKCs, atypical PKCs; GLUT, glucose transporter; TBC1D1, Tre-2/USP6, BUB2, cdc16 domain family member 1; AS160, Akt
substrate of 160 kDa; CBD, calmodulin-binding domain. [Adapted from Ref. 66.]

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310 MOLECULAR MECHANISMS REGULATING GLUCOSE UPTAKE IN MUSCLE
composed of a catalytic ␣-subunit and regulatory ␤- and
␥-subunits. The ␣- and ␤-subunits each exist in two isoforms
(␣1, ␣2, ␤1, and ␤2), and the ␥-subunit exists in three isoforms
(␥1, ␥2, and ␥3). AMPK is activated by phosphorylation by one
or more upstream kinases, including LKB1 (20, 39). A previ-
ous study (53) involving incubation with the AMP-analog
5-aminoimidazole-4-carboxamide ribonucleoside (AICAR)
have shown that activation of AMPK is positively correlated
with increased skeletal muscle glucose uptake. This increase in
glucose uptake by AICAR stimulation is lost in mouse models
deficient in AMPK ␣2- or ␥3-subunits (10, 33). Some studies
(1, 28, 30, 33, 57, 69) have shown that mice overexpressing
a dominant negative AMPK-␣2 construct in muscle or
AMPK-␣1 and -␤ KO mice have impaired exercise-stimulated
glucose uptake. However, other studies using mouse models
with ablated AMPK activity have demonstrated that inhibition
of AMPK has little or no effect on exercise-induced glucose
uptake (15, 33, 55) or exercise-stimulated glucose uptake in
vivo (50). Thus, whether AMPK is necessary for exercise-
stimulated glucose uptake is not fully understood. In a mouse
muscle-specific LKB1 KO model, AMPK-␣2 activation was
completely inhibited and exercise-stimulated glucose uptake
was severely blunted (41, 67). This impairment could be due to
decreased activation of AMPK and one or more of the AMPK-
related kinases that are substrates of LKB1, for example,
sucrose nonfermenting AMPK-related kinase, which is in-
volved in exercise-induced glucose uptake (42). However, the
role of LKB-1 in exercise-stimulated glucose uptake is debat-
able (31). Whereas previous studies (41, 67) have shown that
exercise-stimulated glucose uptake was impaired in LKB-1 KO
mice, another recent study (31) showed that glucose uptake
during treadmill running was similar, if not higher, in LKB-1
KO mice compared with wild-type control mice. An additional
study (23) has also shown that muscle-specific deletion of
LKB1 only partially inhibits exercise-stimulated glucose trans-
port. These data suggest that while AMPK and LKB1 are
important in the regulation of exercise-stimulated glucose up-
take, there are several potential mechanisms involved in the
control of exercise-stimulated glucose transport in skeletal
muscle.
Ca2⫹/Calmodulin-Dependent Protein Kinases
A fundamental part of skeletal muscle contraction is the
increase in intracellular Ca2⫹ concentration. More recently,
studies have indicated Ca2⫹/calmodulin signaling and Ca2⫹/
calmodulin-dependent protein kinases (CaMKs) as critical
components of Ca2⫹- and exercise-stimulated skeletal muscle
glucose uptake. Incubation of rat skeletal muscle with the
Ca2⫹/calmodulin inhibitor KN-93 decreased skeletal muscle
glucose transport in response to contraction (86). Incubation
with KN-93 also significantly inhibited exercise-induced CaM-
KII phosphorylation in the absence of AMPK inhibition. This
suggests that CaMKs regulate glucose uptake independently of
AMPK signaling (83, 86). These studies also showed that
overexpression of constitutively active CaMKK␣ in mouse
skeletal muscle increased AMPK Thr172 phosphorylation and
skeletal muscle glucose uptake (83). However, this increase in
glucose uptake was also observed in muscle overexpressing
dead AMPK-␣2 and thus is likely independent of AMPK
activation. In contrast, another study (30) using isolated skel-
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etal muscle showed that inhibition of CaMK signaling with
KN-93 inhibited contraction-induced skeletal muscle glucose
uptake through an AMPK-dependent signaling pathway. These
data suggest that CaMKs play important roles in the regulation
of contraction-induced skeletal muscle glucose uptake, but the
role of AMPK in the regulation of Ca2⫹/calmodulin-mediated
increases in skeletal muscle glucose uptake is unclear. Re-
cently, electroporation of a specific CaMKII inhibitor into
mouse tibialis anterior muscle reduced exercise-stimulated
glucose uptake by 30% (84). However, a separate study (29)
found that increases in Ca2⫹ concentration in muscle caused
very little increase in glucose uptake when the contractile
response of the muscle was impaired. These data point to an
indirect effect of Ca2⫹ on muscle glucose uptake.
Downstream Targets of Insulin- and Exercise-Stimulated
Contraction (AS160, TBC1D1, and Rac1)
The downstream signaling pathways for insulin and exercise
have revealed a converging signal for insulin- and the exercise-
stimulated glucose uptake in skeletal muscle. Some of the
molecules involved in this point of convergence are AS160 and
TBC1D1. The link between AS160 and TBC1D1 as well as
GLUT4 translocation involves Rab proteins. Rab proteins are
members of the Ras small GTPase superfamily (81). These
proteins are involved in many membrane trafficking events,
and active Rabs recruit various effectors that are involved in
vesicle budding, tethering, and fusion and therefore also in
GLUT4 translocation (34, 63, 81). In addition to the well-
established roles of Rab proteins, there is evidence that the Rho
family GTPase Rac1 is involved in both insulin- and exercise-
stimulated GLUT4 translocation (71, 72). Mice deficient in
Rac1 (Rac1 KO mice) have decreased insulin-stimulated
#
0.06 * *
PCr recovery rate constant (s-1)
0.05
0.04
0.03
0.02
0.01
0.00
C T2D
Fig. 2. Exercise restores mitochondrial function in type 2 diabetic (T2D)
subjects. In vivo mitochondrial function was measured in vastus lateralis
muscle and expressed as the rate constant (in s⫺1) before (solid bars) and after
training (open bars). A high rate constant reflects high in vivo mitochondrial
function. Pre- and posttraining leg extension exercise was performed at 0.5 Hz
to an acoustic cue on a magnetic resonance-compatible ergometer and a weight
corresponding to 60% of the predetermined maximum. Postexercise phospho-
creatine (PCr) resynthesis is driven almost purely oxidatively, and the resyn-
thesis rate reflects in vivo mitochondrial function. Data are expressed as means ⫾
SE. #Data for T2D subjects were significantly different from those of the
control (C) group. *Posttraining was significantly different from pretraining.
[Adapted from Ref. 52.]
 Refresher Course
MOLECULAR MECHANISMS REGULATING GLUCOSE UPTAKE IN MUSCLE 311

GLUT4 translocation (71, 83), and Rac1 inhibition decreased increases TBC1D1 PAS phosphorylation in skeletal muscle (2,
contraction-stimulated glucose uptake in mouse skeletal mus- 73, 80), but, unlike AS160, TBC1D1 can regulate insulin-
cle (72). stimulated glucose transport through a PAS-independent mech-
AS160. AS160 regulates insulin-stimulated GLUT4 translo- anism (2). Studies (2, 80) have shown that distinct mutations of
cation (5, 68, 74). It is phosphorylated on six different phos- TBC1D1 differentially regulate insulin- and exercise-stimu-
pho-Akt-substrate (PAS) sites in response to both insulin and lated glucose transport in skeletal muscle. These data suggest
exercise in skeletal muscle (5, 43, 76). Studies have shown that that TBC1D1 regulates both insulin- and exercise-stimulated
AS160 PAS phosphorylation is increased after prolonged ex- glucose uptake through distinct phosphorylation sites. Taken
ercise in both humans (12, 70, 76) and rats (6, 14). Studies have together, these data suggest that TBC1D1, along with AS160,
shown that AMPK phosphorylates AS160 (PAS site) in re- may also serve as a point of convergence for the regulation of
sponse to AICAR and exercise in skeletal muscle (43) and that GLUT4 translocation via both insulin- and exercise-stimulated
mutation of four PAS sites significantly inhibits both insulin glucose uptake in skeletal muscle.
and exercise-induced glucose uptake (44). Additional data
have demonstrated that mutation of the calmodulin-binding Effects of Chronic Exercise Whole Body Metabolic Health
domain on AS160 significantly inhibits exercise-stimulated
glucose uptake but not insulin-stimulated glucose uptake (45). Exercise training has important therapeutic implications for
Interestingly, whole body KO of AS160 does not result in a people with type 2 diabetes. Here, we will discuss several
significant increase in glucose transport in skeletal muscle (8). adaptations of skeletal muscle to chronic exercise and how
These data clearly show that both phosphorylation and calmod- these adaptations can improve metabolic health in people with
ulin binding on AS160 are involved in the regulation of type 2 diabetes, specifically by improving mitochondrial func-
exercise-stimulated glucose uptake. These data also suggest tion and increasing GLUT4 protein expression.
that while AS160 may serve as a point of convergence for both
insulin- and exercise-dependent signaling in the regulation of Effects of Chronic Exercise on Skeletal Muscle Mitochondria
glucose uptake, other proteins may be involved in this regula-
tion of glucose uptake. People with type 2 diabetes have been reported to have
TBC1D1. Recent studies (5, 36, 37, 43, 64, 73, 77) have smaller, damaged, or dysfunctional mitochondria (59) and
identified TBC1D1, the paralog of AS160, as another potential decreased expression of peroxisome proliferator-activated re-
molecular link among signaling pathways converging on ceptor-␥ coactivator-1␣, a marker of mitochondrial biogenesis
GLUT4 translocation in skeletal muscle. TBC1D1 and AS160 (47, 55). Skeletal muscle mitochondrial dysfunction has also
are 47% identical overall and have several comparable struc- been linked with insulin resistance and type 2 diabetes (59),
tural features. TBC1D1 was first identified in adipocytes in although more studies are needed to directly connect mitochon-
culture but is highly expressed in skeletal muscle (64). Insulin drial deficits with impaired muscle glucose metabolism. It is

Pre Post Pre Post

A B
Glucose Concentration (mmol)

9
GLUT4 protein content (a.u.)

*
24 hr Average Blood

8
4
7
*
3
6
2 Fig. 3. GLUT4 and mitochondrial markers
5
increased after 2 wk of low-volume high-
1 4
intensity interval training. A–D: 2 wk of
high-intensity training increased GLUT4
0 protein content in skeletal muscle (A), glyce-
Pre Post Pre Post mic control (average blood glucose) as mea-
sured by continuous glucose monitoring (B),
citrate synthase (CS) activity (C), and mito-
C D chondrial markers in skeletal muscle (D).
Pre
3.0 Pre, before training; Post, after training;
Protein content (a.u.)

*
(mmol•kg protein-1•hr-1)

p=0.06 Post
4 2.5 NDUFA9, NADH dehydrogenase (ubiqui-
* none) 1␣ subcomplex subunit 9. Values are
2.0 * * p=0.12 means ⫾ SD; n ⫽ 7. *P ⬍ 0.05. [Adapted
CS activity

3
1.5 from Ref. 46.]
2
1.0

1 0.5

0.0
0
9

α
ni
FA

ei

tI

se
bu

Pre Post
ot

ni
U

ha
pr
su

bu
D

nt
IN

su
a

sy
kD

e
ex

or

IV

TP
pl

70

ex

A
om

III
II

pl
ex
ex

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C

pl
pl

C
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C
C

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312 MOLECULAR MECHANISMS REGULATING GLUCOSE UPTAKE IN MUSCLE
also unclear if the mitochondrial defect precedes the develop-
ment of type 2 diabetes or vice versa.
Endurance exercise training has been shown to increase
mitochondrial content and activity (22, 52). A recent study (52)
examined the effects of exercise training in people with type 2
diabetes and determined if exercise could restore mitochondrial
content and function and insulin sensitivity in a patient popu-
lation. Eighteen male subjects underwent 12 wk of exercise
training. Subjects exercised 3 times/wk, 2 times/wk on a cycle
ergometer (55% of their maximal O2 consumption), and 1
time/wk with resistance exercise (at 75% maximal voluntary
contraction). After 12 wk of exercise, the defects previously
observed in skeletal muscle mitochondrial activity in people
with type 2 diabetes were completely negated. Interestingly,
this restored mitochondrial function (Fig. 2) was correlated to
improved insulin-stimulated glucose disposal (52). These data
indicate that the restoration of mitochondrial function in type 2
diabetic patients accompanies the improved skeletal muscle
insulin sensitivity.
Effects of Chronic Exercise on Skeletal Muscle GLUT4
Expression
It is well established that endurance exercise training
increases skeletal muscle GLUT4 (22, 63). The increase in
skeletal muscle GLUT4 causes an increase in skeletal mus-
cle glucose uptake (24, 26, 47, 63). Most studies that have
examined the therapeutic effects of exercise in people with
type 2 diabetes have focused on low- to moderate-intensity
aerobic exercise, which has been established as an effective
strategy to improve the metabolic health of people with type
2 diabetes (9). The recommended amount of exercise for
people with type 2 diabetes is 150 min of moderate intensity
exercise per week (9). However, the amount of exercise
required for improvements in whole body and skeletal
muscle metabolic health is debatable. Recent studies have
examined if the effects of low-volume high-intensity inter-
val training (HIT), a time-efficient strategy to improve
health and fitness, could be applied to people with type 2
diabetes as an intervention to improve glucose regulation
and skeletal muscle metabolism (82). This study involved
14 people with type 2 diabetes (45). Eight of these subjects
underwent HIT for 2 wk, where they trained on a cycle
ergometer a total of six times over the 2-wk period. Each
session consisted of a 5-min warmup, 10 ⫻ 60 s of cycling
at 90% maximal effort with 60 s of recovery, and a 5-min
cooldown. After 2 wk of HIT, people with type 2 diabetes
had a marked increase in skeletal muscle GLUT4 expression
and a significant decrease in blood glucose concentrations.
Markers of mitochondrial activity, such as citrate synthase
activity and expression of complex I, II, and III, were also
significantly increased after 2 wk of HIT (Fig. 3). These data
indicate that only 2 wk of HIT, where the weekly training
time was 50% lower than the recommended guidelines for
exercise in type 2 diabetic patients (9), increased glucose
uptake and improved mitochondrial function in people with
type 2 diabetes and improved whole body metabolism. This
study indicated that HIT is a potential time-efficient exercise
strategy for the treatment of type 2 diabetes.
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Summary
In summary, exercise is critical in the treatment and preven-
tion of type 2 diabetes. Acute exercise activates alternative
molecular signals that can bypass defects in insulin signaling in
skeletal muscle, resulting in an insulin-independent increase in
glucose uptake. Exercise training results in increased skeletal
muscle mitochondria and GLUT4 protein expression, which
are associated with improved skeletal muscle insulin sensitivity
and whole body metabolic health. Exercise-induced adapta-
tions to skeletal muscle are essential to prevent and combat
type 2 diabetes.
GRANTS
This work was supported by an American College of Sports Medicine
Research Endowment Grant (to K. I. Stanford), Mary K. Iacocca Fellowship
(to K. I. Stanford), and National Institutes of Health Grants R01-AR-42238 (to
L. J. Goodyear), R01-DK-101043 (to L. J. Goodyear), and 5-P30-DK-36836
(Diabetes Research Center, Joslin Diabetes Center).
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
Author contributions: K.I.S. drafted manuscript; K.I.S. and L.J.G. edited
and revised manuscript; K.I.S. and L.J.G. approved final version of manuscript.
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