artigo 64 - exercise training-induced improvements in insulin action

8/11/2019 Artigo 64 - Exercise Training-Induced Improvements in Insulin Action

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REVIEW

Exercise training-induced improvements in insulin action

J. A. Hawley and S. J. Lessard

Exercise Metabolism Group, School of Medical Sciences, RMIT University, Bundoora, Vic., Australia

Received 13 July 2007,

accepted 17 August 2007

Correspondence: J. A. Hawley,

Exercise Metabolism Group,

School of Medical Sciences, RMIT

University, PO Box 71, Plenty

Road, Bundoora, Vic. 3083,

Australia.

E-mail: [email protected]

Abstract

Individuals with insulin resistance are characterized by impaired insulin

action on whole-body glucose uptake, in part due to impaired insulin-stim-

ulated glucose uptake into skeletal muscle. A single bout of exercise increases

skeletal muscle glucose uptake via an insulin-independent mechanism that

bypasses the typical insulin signalling defects associated with these condi-

tions. However, this insulin sensitizing effect is short-lived and disappears

after 48 h. In contrast, repeated physical activity (i.e. exercise training)results in a persistent increase in insulin action in skeletal muscle from obese

and insulin-resistant individuals. The molecular mechanism(s) for the

enhanced glucose uptake with exercise training have been attributed to

the increased expression and/or activity of key signalling proteins involved in

the regulation of glucose uptake and metabolism in skeletal muscle. Evidence

now suggests that the improvements in insulin sensitivity associated with

exercise training are also related to changes in the expression and/or activity

of proteins involved in insulin signal transduction in skeletal muscle such as

the AMP-activated protein kinase (AMPK) and the protein kinase B (Akt)

substrate AS160. In addition, increased lipid oxidation and/or turnover is

likely to be another mechanism by which exercise improves insulin sensi-

tivity: exercise training results in an increase in the oxidative capacity ofskeletal muscle by up-regulating lipid oxidation and the expression of pro-

teins involved in mitochondrial biogenesis. Determination of the underlying

biological mechanisms that result from exercise training is essential in order

to define the precise variations in physical activity that result in the most

desired effects on targeted risk factors, and to aid in the development of such

interventions.

Keywords AMPK, AS160, insulin sensitivity, lipid metabolism, mitochon-

drial biogenesis, muscle glycogen.

Historical perspective

In recent decades intense research effort has focused on

understanding the signalling mechanisms leading to

exercise-stimulated glucose transporter 4 (GLUT4)

translocation and the increased skeletal muscle glucose

uptake and metabolism that follow a single bout of

exercise. Results from many studies undertaken by

independent laboratories demonstrate that muscle con-

traction stimulates glucose in the complete absence of

insulin; that the maximal effects of contraction and

insulin are additive; and that contraction and insulin

stimulate glucose transport by separate pathways (for

reviews, see, Holloszy & Hansen 1996, Ivy 1987,

Henriksen 2002, Sakamoto & Goodyear 2002, Zierath

2002, Holloszy 2003, 2005). Following exercise there is

a prolonged and persistent increase in glucose uptake by

skeletal muscle(Ivy & Holloszy 1981, Young et al. 1983,

Ren et al. 1993). Reversal of this increase in muscle

insulin sensitivity after exercise occurs simultaneously

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with muscle glycogen repletion and can be accelerated

by carbohydrate feeding or attenuated by keeping

muscle glycogen content low by fasting (Young et al.

1983). If adequate carbohydrate is supplied throughout

the post-exercise recovery period, muscle glycogen

stores can be supercompensated to levels that are

twofold higher than the fed sedentary state (Bergstrom

& Hultman 1966, Cartee et al.1989). A contemporaryobjective of exercise biochemistry is to understand the

molecular mechanisms by which the various metabolic

pathways involved in substrate turnover are regulated

during exercise and identify how these acute signals

may initiate responses that form the basis of the

adaptations to chronic exercise (Hawley et al. 2006).

In this brief review, we will focus on several of the key

putative signalling proteins that are likely to be

responsible for some of the exercise training-induced

improvements in insulin action.

Exercise: an effective therapeutic interventionfor enhancing insulin sensitivity

Individuals with insulin resistance and type 2 diabetes

are characterized by impaired insulin action on whole-

body glucose uptake, in part due to impaired insulin-

stimulated glucose uptake in skeletal muscle (Zierath

et al. 1996). However, acute exercise increases glucose

uptake in skeletal muscle via an insulin-independent

mechanism that bypasses the insulin signalling defects

associated with these conditions (Wallberg-Henriksson

& Holloszy 1984, DeFronzo et al. 1987, Ivy 1987,

Cortezet al. 1991, Zierath et al. 2000, Christ-Roberts

et al.2003, Richteret al.2004, OGormanet al.2006).The acute increase in glucose transport in response to a

single bout of whole-body exercise is mediated by a

variety of intramyocellular signalling events including

increased insulin receptor signalling, activation of the

AMP-activated protein kinase pathway (AMPK), Akt/

protein kinase B phosphorylation, nitric oxide produc-

tion and calcium-mediated mechanisms involving Ca2+/

calmodulin-dependent protein kinase (CaMK) and

protein kinase C (PKC) (Sakamoto & Goodyear 2002,

Jessen & Goodyear 2005). As the insulin-sensitizing

effects of an acute exercise bout are short-lived and

persist for only 48 h if another bout of exercise is not

undertaken (Ivy et al. 1983, Etgen et al. 1993, Wo-

jtaszewski et al. 2002), the pertinent question is can

exercise training prevent the insulin-resistant state that

precedes type 2 diabetes? The resounding answer is

yes (for reviews, see, Goodyear & Kahn 1998,

Albright et al. 2000, Hawley 2004, Hawley & Houm-

ard 2004). Here we summarize evidence to show that

exercise training produces metabolic adaptations that

result in sustained improvements in whole-body and

muscle insulin sensitivity.

Effects of exercise training on insulin

signalling: IRS-1, IRS-2 and PI3K

Exercise training results in a rapid increase in the

expression of both GLUT-4 mRNA and protein in

skeletal muscle (Kraniouet al.2006) and these changes

have been associated with improved glucose uptake and

metabolism (Delaet al.1993, Ren et al. 1994, Hansenet al.1995). The role of the exercise-induced increase in

GLUT protein content on glucose transport has been

reviewed previously (Ivy 1997, 2004) and will not be

discussed in detail here. Theimmediate effects of exercise

on glucose action occur primarily through the level of

GLUT-4 trafficking (Ploug et al. 1998; Thong et al.

2005) rather than through any enhancement of insulin

signalling at the level of the insulin receptors, insulin

receptor substrate (IRS)-1, IRS-2 or phosphatidylinosi-

tol-3-kinase (PI3K) (Treadwayet al. 1989, Wojtaszewski

et al.2000, Howlett et al.2002). Because the effects of

exercise on insulin sensitivity persist for between 16 (Ren

et al. 1994, Chibalin et al. 2000) and 48 h (Bogardus

et al. 1983) after the last exercise bout, measurements

made at these times in individuals who undertake regular

training reflect changes in expression or activity of a

variety of signalling proteins involved in the regulation

of skeletal muscle glucose uptake (Zierath 2002).

The results of studies of the effects of exercise training

on the insulin receptor substrates IRS-1 and IRS-2 are

highly variable, possibly because of differences in the

training stimulus (the mode, intensity and duration of

exercise), prior dietary intake, training status and the

muscles and/or fibre type being assessed (Chibalinet al.

2000, Howlett et al. 2002, 2006, 2007, Frosig et al.2007). For example, in insulin-sensitive rodents who

underwent either 1 or 5 days of exhaustive swimming

(6 h day)1), IRS-1 protein expression tended to be

increased after a day of exercise, whereas it was reduced

16 h after the chronic training regimen (Chibalin et al.

2000). Yuet al.(2001) reported similar results for IRS-

1 protein levels in muscle for humans engaged in

endurance-training programmes. In contrast, a single

bout of resistance training results in a decrease in basal

(but not insulin-stimulated) IRS-1 tyrosine phosphory-

lation, yet following 7 days of training, basal IRS-1

phosphorylation was similar to pre-training values

(Howlettet al.2007). With regard to IRS-2 expression,

levels of this protein are increased threefold in rodent

muscle 16 h after a single bout of prolonged (6 h)

swimming but return to pre-training levels 16 h after

5 days of repeated training bouts (Chibalinet al.2000).

In agreement with the results from animal studies,

OGorman et al. (2006) have reported that IRS-1 and

IRS-2 protein expression are unaffected by short-term

(7 days) exercise training in obese diabetic subjects,

while Yuet al.(2001) showed that in skeletal muscle of

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humans habitually involved in endurance run-training,

IRS-2 was actually decreased to levels below sedentary

individuals. Taken collectively, these results suggest that

exercise has diverse effects on this receptor substrate

that involve changes in both signal transduction and

protein expression. In the final analyses it may be that

IRS-2 plays only a minor role in both insulin- and

exercise-stimulated glucose transport in skeletal muscle,as has been previously suggested (Higaki et al. 1999).

Clearly time-course studies of the effects of different

stimuli (endurance and resistance exercise) are needed

to fully elucidate the role of exercise training on IRS-1

and IRS-2 in skeletal muscle.

While the effects of exercise on IRS-1 and IRS-2 are

inconsistent, improvements in whole-body insulin-

mediated glucose uptake after exercise training have

been attributed to enhanced intracellular signalling via

PI3K activity in both rodent (Chibalin et al. 2000) and

human models (Houmard et al. 1999, Kirwan et al.

2000). Such findings are clinically relevant because PI3K

activity is decreased in skeletal muscle from insulin-

resistant subjects and patients with type 2 diabetes

(Goodyear et al. 1995, Bjornholm et al. 1997, Kim et al.

1999). Houmardet al.(1999) demonstrated that 7 days

of exercise training (1 h d)1 at 75% maximal oxygen

consumption) improved whole-body glucose disposal

and that this increase in insulin sensitivity was accom-

panied by an increase in insulin-stimulated PI3K activity.

Kirwan et al. (2000) reported that insulin-stimulated

PI3K activity was greater in skeletal muscle from

endurance-trained vs. sedentary individuals, and when

these two cohorts were compared together, PI3K acti-

vation was correlated with both glucose disposal andwhole-body aerobic capacity. Recently, Frosig et al.

(2007) reported that 3 weeks of one-legged knee-exten-

sor exercise in healthy subjects increased insulin-stimu-

lated glucose uptake by 60% in the trained limb, but that

training reduced IRS-1-associated PI3K activity in both

basal and insulin-stimulated muscle. The physiological

significance of the exercise-induced decrease in basal and

insulin-stimulated IRS-1-associated PI3K activity in

muscle from healthy subjects is not presently clear.

However, it would appear that the major effects of

repeated contractions on the insulin signalling cascade in

insulin-resistant muscle are confined to a training-

induced restoration of insulin-stimulated PI3K activity

and/or phosphorylation, and not to increases in the

protein expression of the canonical insulin receptor

substrates, IRS-1 or IRS-2.

Effects of exercise training on the

AMP-activated protein kinase

The up-regulation of the AMP-activated protein kinase

(AMPK) is another potential mechanism by which

exercise training improves insulin sensitivity. In addition

to acute activation of AMPK due to muscle contraction,

exercise training results in an up-regulation of AMPK

protein. Lessard et al. (2007) reported that in a rodent

model of insulin resistance, the high-fat fed rat, 4 weeks

of endurance training (treadmill running) resulted in a

significant increase in the protein expression and activity

of thea1 but not thea2 isoform. In healthy individuals,3 weeks of endurance training increases the protein

content of the AMPK a1, b2 and c1 subunits (Frosig

et al.2004). Seven weeks of exercise training (treadmill

running) in obese Zucker rats results in a 1.5-fold

increase in AMPKa1 protein expression and restores

impaired AMPK activation to the level of lean controls

(Sriwijitkamolet al. 2006). Pold et al. (2005) observed

that 8 weeks of treadmill running in Zucker fatty rats

produced similar improvements in insulin sensitivity as

daily 5-aminoimidazole-4-carboxamide-1-b-d-ribofura-

noside (AICAR) administration. However, unlike leptin-

deficient (ob/ob mouse) and leptin receptor-deficient (fa/

fa Zucker rat) rodent models of diabetes, humans with

type 2 diabetes do not exhibit decreased AMPK subunit

expression or activation compared with healthy controls

(Wojtaszewskiet al. 2005). Wojtaszewski et al. (2005)

investigated the effect of strength training on the isoform

expression and heterotrimeric composition of the AMPK

in human skeletal muscle from 10 patients with type 2

diabetes and seven healthy controls. Subjects undertook

6 weeks of strength training with one leg while the other

leg remained untrained. Muscle biopsies were obtained

before and after the training period. Basal AMPK

activity and mRNA and protein expression of both

catalytic (a1 and a2) and regulatory (b1, b2, c2, c3)AMPK isoforms were independent of health status,

whereas the protein content ofa1 (+16%), b2 (+14%)

and c1 (+29%) were higher with the c3 content lower

()48%) in trained compared with untrained muscle.

Even so, Wojtaszewskiet al. (2005) observed a compa-

rable increase in the expression of the a1, b2 and c3

subunits of AMPK in response to 6 weeks of resistance

training in patients with type 2 diabetes and healthy

controls.

It is also possible that exercise-induced up-regulation

of AMPK mediates its effects through distal components

of the insulin signalling cascade. In this regard, an Akt

substrate with molecular weight of 160 kDa (AS160)

and a molecular signature of a Rab-GTPase-activating

protein (GAP) has recently been identified as an

important regulator of GLUT4 traffic (Kane et al.

2002), promoting translocation of GLUT4-containing

vesicles to the plasma membrane (Sano et al. 2003).

Rab-GAP domains modulate the activity of Rab pro-

teins, which are involved in the regulation of several

membrane transport steps, including vesicle budding,

motility, tethering and fusion (Zerial & McBride 2001).

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Insulin stimulation of skeletal muscle leads to phos-

phorylation of AS160, a process dependent on Akt2

(Brusset al.2005, Bouzakriet al.2006). AS160 is also

phosphorylated in response to exercise in human

skeletal muscle (Deshmukh et al. 2006, Frosig et al.

2007) and after in vitro contraction in rodent skeletal

muscle (Brusset al.2005, Kramer et al. 2006). Lessard

et al. (2007) found that 4 weeks of endurance trainingincreased IRS1-associated PI3K activity and normalized

impairments to total protein levels in the Akt/AS160/

GLUT4 signalling pathway caused by high-fat feeding.

Frosiget al.(2007) reported that both basal and insulin-

stimulated AS160 phosphorylation were increased in

human skeletal muscle after 3 weeks endurance training

and attributed this to changes in AMPK activity acting

upstream of AS160. Interestingly, when AS160 phos-

phorylation was expressed relative to total protein

content, the effect of training on this protein disap-

peared (Frosiget al.2007). Thus, while AS160 may be a

critical point of convergence for insulin- and exercise-

mediated glucose uptake in skeletal muscle (Deshmukh

et al. 2008), the precise role to explain the training-

induced effects on AS160 signalling on glucose trans-

port is not known.

Aside from its role in regulating both insulin-depen-

dent and -independent glucose uptake in skeletal muscle,

AMPK is also a regulator of lipid metabolism. AMPK

activation results in the up-regulation of fatty acid (FA)

oxidation in skeletal muscle via phosphorylation of its

target protein, acetyl CoA carboxylase (ACC), the

enzyme that catalyses the rate-limiting step in the

conversion of acetyl CoA to malonyl CoA. AMPK-

induced phosphorylation at ser-218 inhibits the actionof ACC and results in decreased cellular malonyl CoA

levels. As malonyl CoA is a potent inhibitor of CPT1, a

reduction in malonyl CoA alleviates the inhibition of

CPT1 and consequently increases the transfer of FA-

CoA into the mitochondria for oxidation. Fatty acid

uptake and oxidation are thought to be mismatched in

type 2 diabetes and obesity, and increased capacity to

oxidize lipids is associated with improved insulin sensi-

tivity (Bruceet al. 2003, 2006, Goodpasteret al. 2003,

Perdomoet al.2004). Therefore, it seems plausible that

AMPK-induced increases in FA oxidation may be an

additional mechanism by which AMPK activation

improves skeletal muscle insulin sensitivity.

Effects of exercise training on lipid status

The regulation of lipid turnover and utilization is a

mechanism by which exercise training may improve

insulin sensitivity (Bruce & Hawley 2004). Exercise

training results in an increase in the oxidative capacity

of skeletal muscle by up-regulating the expression of

proteins involved in mitochondrial biogenesis such as

peroxisome proliferator-activated receptor c coativator

(PGC1), peroxisome proliferator-activated receptor a

(PPAR-a) and nuclear respiratory factor 1 (Gollnick &

Saltin 1982, Hawley 2002, Irrcher et al.2003). Oxida-

tive enzyme capacity is low in individuals with insulin

resistance, which is thought to contribute to a state of

metabolic inflexibility that does not permit the tran-

sition between fasting and postprandial states observedin healthy, insulin-sensitive individuals (Storlien et al.

2004). This inflexibility, in turn is thought to contribute

to the aberrant skeletal muscle glucose and lipid

metabolism that is associated with insulin resistance

and type 2 diabetes. Furthermore, the maximal activ-

ities of several skeletal muscle oxidative enzymes (i.e.

citrate synthase) are good predictors of whole-body

insulin sensitivity, suggesting that treatments that

increase oxidative capacity may also improve insulin

sensitivity (Bruce et al. 2003). In support of this

contention, Goodpasteret al.(2003) demonstrated that

the strongest predictor of insulin sensitivity following

endurance training in obese individuals was enhanced

whole-body lipid oxidation. Furthermore, increased

oxidative capacity following exercise training was

recently associated with increased CPT1 activity and

decreased ceramide and diacylglycerol content in the

muscle of obese individuals (Bruce et al. 2006). The

findings by Bruce et al. (2006) suggest that exercise

training may improve muscle insulin sensitivity by

increasing the proportion of lipids targeted for oxida-

tion, thereby reducing the accumulation of lipid species

that are known to inhibit insulin signal transduction, as

has recently been proposed (Hawley & Lessard 2007).

In direct support of this contention, we (Lessard et al.2007) have shown that 4 weeks of exercise training

attenuated high-fat, diet-induced increases in muscle

lipid storage. Furthermore, in that study (Lessard et al.

2007) exercise training was associated with increased

rates of palmitate oxidation and elevated PGC-1

expression (i.e. mitochondrial biogenesis).

Finally, despite lower rates of fatty acid oxidation at

rest, it is noteworthy that individuals with insulin

resistance are readily able to utilize lipids during

exercise. Both obese sedentary males (Goodpaster et al.

2002) and females with abdominal adiposity (Horowitz

& Klein 2000) have higher rates of FA oxidation during

submaximal exercise compared with their lean seden-

tary, fitness-matched counterparts. Thus, the acute

molecular/cellular signalling events that accompany

contraction act to override the metabolic constraints

observed in individuals with insulin resistance at rest

(i.e., metabolic inflexibility) and predispose muscle

towards a preference for lipid oxidation (i.e. metabolic

flexibility). It is tempting to speculate that the oxidation

and turnover of muscle lipids may represent a mecha-

nistic link between mitochondrial function, lipid

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the onset of diabetes and its secondary complications.

As skeletal muscle is the major source for insulin-

stimulated glucose uptake, any treatment targeted to

improve glucose uptake in this tissue will improve

whole-body glucose homeostasis. There is irrefutable

evidence that exercise training is an effective therapeutic

intervention to increase insulin action in skeletal muscle

from obese and insulin-resistant individuals. There areseveral ways in which exercise training may improve

skeletal muscle glucose uptake. These include up-

regulation of GLUT4 expression, chronic activation of

AMPK, facilitation of insulin signal transduction at the

level of PI3K and AS160, as well as increases in the

expression of several proteins involved in glucose and

lipid utilization and turnover (Fig. 1). Determination of

the underlying biological mechanisms that result from

exercise training is essential in order to define the

precise variations in physical activity that result in the

most desired effects on targeted risk factors and to aid

in the development of such interventions.

Conflicts of interest

The authors declared no conflicts of interest.

This review was supported by a grant from the Australian

Research Council (DP0663862) to the authors.

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