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Aerobic exercise training versus the aetiology of insulin resistance

Sophie E. Yeoa; Robert H. Cokerab
a
Nutrition, Metabolism, and Exercise Laboratory, University of Arkansas for Medical Sciences, b
Geriatric Research, Education, and Clinical Center, Central Arkansas Veterans Healthcare System,
Little Rock, AR, USA

To cite this Article Yeo, Sophie E. and Coker, Robert H.(2008) 'Aerobic exercise training versus the aetiology of insulin
resistance', European Journal of Sport Science, 8: 1, 3 — 14
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 European Journal of Sport Science, January 2008; 8(1): 3
14

REVIEW ARTICLE

Aerobic exercise training versus the aetiology of insulin resistance

SOPHIE E. YEO1 & ROBERT H. COKER1,2

1
Nutrition, Metabolism, and Exercise Laboratory, University of Arkansas for Medical Sciences, and 2Geriatric Research,
Education, and Clinical Center, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA

Abstract
Type 2 diabetes represents an epidemic disease that has become a widespread healthcare problem throughout the world.
Downloaded By: [European College of Sport Science] At: 08:49 2 August 2010

The prevalence of a sedentary lifestyle and excess caloric intake promotes the aetiology of insulin resistance that results in
the development of the metabolic condition, Type 2 diabetes. Despite numerous investigations that have demonstrated the
positive influence of aerobic exercise training on a reduction in the severity of insulin resistance, many of these exercise
programmes yield benefits that are only short-lived and promote only modest reductions in the severity of the disease
aetiology. Therefore, the efficacy of exercise training as a therapeutic intervention against the development of Type 2
diabetes rests on its ability to normalize insulin resistance in the liver and skeletal muscle using a progressive approach that
combines the beneficial influences of exercise training and weight loss.

Keywords: Hepatic, muscle, mitochondria, lipid, adipokines, inflammation

Introduction the prevention and management of Type 2 diabetes

Type 2 diabetes is a complex metabolic disorder
characterized by persistent hyperglycaemia and in-
sulin resistance (Reaven, 1988). Currently, a stag-
gering 246 million people worldwide suffer from
diabetes mellitus, and this figure is predicted to rise
to 380 million by the year 2025 (International
Diabetes Federation, 2007). In Europe alone, 53
million people have Type 2 diabetes (International
Diabetes Federation, 2007), and the total direct
medical cost of the disease is estimated to be e29
billion per year, accounting for 5% of Europe’s
annual healthcare budget (Jonsson, 2002). Type 2
diabetes is associated with a number of severe,
chronic health complications, including visual loss,
renal failure, amputations, loss of functional inde-
pendence, and a higher rate of cardiovascular disease
and mortality (Reaven, 1995). Patients with Type 2
diabetes are also three times more likely to suffer
with depression than non-diabetic individuals
(Harris, 2003). The medical, psychological, and
financial burdens on society have reached epidemic
proportions and, as a result, the efforts involved in
have become increasingly important.
Type 2 diabetes is associated with defects in
insulin action at multiple levels. For example,
suppression of hepatic glucose production is im-
paired, glucose transport into peripheral tissues is
reduced, and insulin secretion can be defective (Ivy,
Zderic, & Fogt, 1999). Initially, insulin resistance in
the liver and skeletal muscle results in a compensa-
tory hyperinsulinaemic response that strives to
maintain glucose homeostasis. Over time, there is a
decline in the secretory capacity of the b-cells that
are responsible for insulin secretion. In addition,
insulin resistance is associated with a clustering of
other metabolic risk factors, including obesity,
hypertension, dyslipidaemia, and cardiovascular dis-
ease (DeFronzo, Bonadonna, & Ferrannini, 1992).
As such, insulin resistance is an important target for
therapeutic intervention in Type 2 diabetes, and a
delineation of the mechanisms that underlie its
development is of primary importance to our under-
standing and management of the disease.
The current rise in the prevalence of Type 2 diabetes
is thought to be a consequence of increasingly

Correspondence: R. H. Coker, Nutrition, Metabolism, and Exercise Laboratory, DWR Institute of Aging, University of Arkansas for
Medical Sciences, 4301 W. Markham, Slot 806, Little Rock, AR 72205, USA. E-mail: cokerrobert@uams.edu

ISSN 1746-1391 print/ISSN 1536-7290 online # 2008 European College of Sport Science
DOI: 10.1080/17461390701832645
 4 S. E. Yeo & R. H. Coker
sedentary lifestyles combined with excess caloric
intake in genetically susceptible individuals (Ivy
et al., 1999). Although genome-wide association
studies suggest that a genetic component exists
(Saxena et al., 2007), it is promising that a number
of genes associated with insulin resistance are highly
responsive to physical activity (Booth & Lees, 2007).
It has been recognized for several years that regular
exercise improves glucose metabolism (Krotkiewski
et al., 1985; Reitman, Vasquez, Klimes, & Nagule-
sparan, 1984). As such, exercise training has been
promoted as an effective strategy for the prevention
and management of Type 2 diabetes (Hawley, 2004).
While considerable progress has been made in recent
years, the distinct role of exercise training towards
lasting changes in systemic insulin resistance con-
tinues to be investigated. Inconsistencies in the
literature are typically due to methodological differ-
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ences associated with study design and data collec-
tion. These differences may include the techniques
used to examine insulin action, exercise training
modalities or the frequency, duration, and intensity
of the exercise training paradigm, whether weight loss
is a component of the exercise training programme,
and/or the metabolic heterogeneity of the volunteers.
For these reasons, exercise prescriptions for the
prevention and treatment of insulin resistance and
Type 2 diabetes lack a validated, practical, and/or
consistent approach. This review provides a summary
and interpretation of research in the field surrounding
the effects of chronic exercise training on insulin
resistance in humans. In addition, the clinical im-
plications of exercise training in the treatment of
insulin resistance and Type 2 diabetes will be dis-
cussed.
Historical studies
The role of exercise in the regulation of glucose
metabolism has been recognized for many years. A
series of studies in frog sartorius muscle dating back
to the 1960s demonstrated that contractile activity
induces glucose uptake in a similar, but independent
way from insulin (Holloszy & Narahara, 1967).
Several positive results from clinical studies followed
these findings (Cochran, Marbach, Poucher, Stein-
berg, & Gwinup, 1966; Hunter & Sukkar, 1968;
Nikkila, Taskinen, Miettinen, Pelkonen, & Poppius,
1968) and led to the advocacy of exercise training for
the treatment of obesity and/or risk of Type 2
diabetes (Gonzalez, 1979).
Positive results from these clinical studies helped
fuel scientific interest in the therapeutic influence of
exercise on glucose homeostasis. As such, the results
of animal studies continued to demonstrate that the
stimulatory effect of acute exercise required the
presence of insulin (Berger, Hagg, & Ruderman,
1975), and the improved sensitivity appeared to take
place primarily in muscle fibres where glycogen was
most depleted (Richter, Garetto, Goodman, &
Ruderman, 1982). Furthermore, these studies sur-
mised that local contraction-induced factors were
largely responsible for the changes in insulin-
mediated glucose utilization and glycogen re-synth-
esis following acute exercise (Richter, Garetto,
Goodman, & Ruderman, 1984). Therefore, results
from these early studies helped support the conten-
tion that acute exercise training helped to alleviate
problems related to the regulatory control of glucose
uptake by the muscle.
As the link between chronic exercise training as a
therapeutic adjunct against the development of
obesity was described, the efficacy of exercise train-
ing to reduce the accumulation of excess lipid, and
treat the aetiology of insulin resistance, gained
interest in the scientific community (Bjorntorp,
1978). In addition, investigators began to suggest a
role for chronic exercise as a preventative strategy
against the age-associated decline in insulin action
(Holloszy, Schultz, Kusnierkiewicz, Hagberg, &
Ehsani, 1986; Seals, Hagberg, Hurley, Ehsani, &
Holloszy, 1984). Furthermore, as little as one week
of exercise training was touted as an effective strategy
against insulin resistance in persons with Type 2
diabetes (Rogers et al., 1988), and the residual
influence of previous exercise was also touted as an
important factor in the enhancement of insulin
sensitivity even in well-trained individuals (Heath
et al., 1983). At this point, the beneficial influence of
exercise training towards insulin action appeared to
rely on potential changes in muscle mass, increased
blood flow to muscles, increased oxidative enzyme
capacity, and enhanced glucose transport (Koivisto,
Yki-Jarviene, & DeFronzo, 1986). As ‘‘intervention-
based’’ studies were leading scientists to directly
examine the impact of acute and chronic exercise
training on insulin resistance, more precise methods
were also being developed to specifically examine
these interventions on endogenous glucose produc-
tion (glucose Ra) and insulin-stimulated glucose
disposal (ISGD).
Methods specific to glucose metabolism
To gain an understanding of the aetiology of Type 2
diabetes, precise techniques are necessary to assess
the effects of an intervention on insulin resistance. A
number of well-established methods are efficacious
in this regard. They include those that provide direct
measurement of the metabolic responses to exogen-
ous insulin, and those that indirectly measure the
action of endogenous insulin (Scheen, Paquot,
Castillo, & Lefebvre, 1994). Initially described by
DeFronzo and colleagues (DeFronzo, Tobin, &

Andres, 1979), the euglycaemic
hyperinsulinaemic
clamp technique is considered the most definitive
method for evaluating peripheral insulin sensitivity
(Ferrannini & Mari, 1998). Typically, this clamp
technique is performed in conjunction with glucose
tracer methodology. In this way, the contribution of
glucose Ra can be subtracted from the exogenous
glucose infusion rate to provide the amount of
ISGD. Due to the relative expense and complexity
of the clamp technique, especially in the clinical
setting, several mathematical equations based on
glucose levels have been proposed as adequate
surrogate measures of whole-body insulin sensitivity
(Belfiore, Iannello, & Volpicelli, 1998; Cederholm &
Wibell, 1990; Katz et al., 2000; Matthews et al.,
1985). Based on cross-sectional data, these methods
are usually closely correlated with ISGD derived
from the euglycaemic
hyperinsulinaemic clamp
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technique. To evaluate the utility of these indirect
approaches versus the clamp technique in detecting
intervention-based changes in insulin sensitivity, we
compared the approaches using the limits of agree-
ment statistical approach from data generated within
our laboratory. We found wider variations in the data
associated with indirect methods of assessment
(Hays et al., 2006a). Although indirect methods
did correlate with the direct assessment of peripheral
insulin sensitivity via the euglycaemic
hyperinsuli-
naemic clamp, wider variations in the data using
methods such as homeostasis model assessment
(HOMA) and/or the oral glucose tolerance test
(OGTT) may limit their efficacy in smaller inter-
vention-based studies (Ferrannini & Mari, 1998).
For these reasons, the present review reports evi-
dence primarily from training studies using the
euglycaemic
hyperinsulinaemic glucose clamp tech-
nique to directly examine changes in insulin action.
In addition to the previously described limitations
of the indirect assessment of peripheral insulin
sensitivity, calculation of hepatic sensitivity to insulin
using estimated or derived methods is challenging at
best (Matsuda & DeFronzo, 1999). Since glucose Ra
is often not completely suppressed under mild
hyperinsulinaemic conditions, especially in indivi-
duals with insulin resistance and Type 2 diabetes,
glucose utilization may be underestimated.
Central to the understanding of glucose metabo-
lism is the regulation of glucose Ra. Under healthy
conditions, pancreatic a- and b-cells respond to the
circulating plasma glucose level by modifying their
secretion of glucagon and insulin, respectively. This
reciprocal control is managed based on the prevail-
ing peripheral/portal glucose concentration, respec-
tively. Glucagon stimulates glucose Ra, while insulin
inhibits it. Even small deviations in plasma glucose
concentration can cause marked changes in the
secretion and concentration of insulin and glucagon
Aerobic exercise vs. aetiology of insulin resistance 5
(Cherrington, 1999). We have recently described an
octreotide, multi-stage euglycaemic clamp technique
whereby levels of glucagon and insulin can be
precisely regulated to selectively examine hepatic
and peripheral insulin action. In these studies,
octreotide is infused to completely suppress endo-
genous insulin and glucagon. In addition, glucagon
is replaced at a basal rate while insulin is infused at
mild and moderate rates to mimic mild and moder-
ate hyperinsulinaemia. This allows the opportunity
to evaluate the suppression of glucose Ra under mild
hyperinsulinaemic conditions (i.e. hepatic insulin
action) and ISGD under moderate hyperinsulinae-
mia simultaneously (Yeo, Kortebein, Williams,
Evans, & Coker, 2006).
Aerobic exercise training and ISGD
Given its mass and capacity for glucose uptake,
skeletal muscle is the primary tissue responsible for
glucose disposal, and has long been considered the
most important tissue where pathological mechan-
isms leading to the development of insulin resistance
originate (DeFronzo, 1988). In fact, skeletal muscle
accounts for 80% of glucose uptake during a
euglycaemic
hyperinsulinaemic clamp, and using
indirect calorimetry it has been determined that
this glucose is primarily stored as muscle glycogen
(Shulman et al., 1990). Muscle glycogen concentra-
tions are 30% less (Shulman et al., 1990), and the
rates of glycogen synthesis are at least 50%, less in
persons with Type-2 diabetes compared with control
volunteers (Carey, Halliday, Snaar, Morris, & Tay-
lor, 2003; Shulman et al., 1990).
Several studies have supported aerobic exercise
training-induced changes in glucose uptake by
skeletal muscle via measurement of ISGD in insu-
lin-resistant individuals (Hughes et al., 1993, 1995;
Perseghin et al., 1996; Sriwijitkamol et al., 2006).
Exercise-induced changes in ISGD have also been
reported in older to elderly individuals, demonstrat-
ing the potential efficacy of aerobic exercise towards
reducing the risk of Type-2 diabetes in ageing (Coker
et al., 2006; DiPietro, Dziura, Yeckel, & Neufer,
2006; Evans et al., 2001; O’Leary et al., 2006).
Moreover, the importance of exercise training-in-
duced changes in glucose clearance by skeletal
muscle has been highlighted by studies utilizing leg
balance techniques in the trained versus contralat-
eral sedentary lower limb in individuals with Type-2
diabetes (Dela et al., 1995). Using this elegant design
in combination with a euglycaemic
hyperinsulinae-
mic clamp, Dela and colleagues (1995) demon-
strated that while training increased glucose
clearance 24 h after exercise, these improvements
were lost within a week of detraining. Thus, the
relative efficacy of exercise training without weight
 6 S. E. Yeo & R. H. Coker
loss in the amelioration of insulin resistance in
skeletal muscle should be addressed.
It is known that factors contributing to defective
insulin signalling in skeletal muscle of insulin-resis-
tant individuals include, but are not limited to,
mitochondrial dysfunction (Heilbronn, Gan,
Turner, Campbell, & Chisholm, 2007), intramus-
cular lipid accumulation (Pan et al., 1995), altered
secretion of adipokines (Kershaw & Flier, 2004),
oxidative stress, and inflammation (Zick, 2003).
Ultimately, such defects result in reduced tyrosine
phosphorylation of key insulin signalling molecules
and impaired insulin signalling to glucose transport
(Shulman, 2004). A brief summary follows; how-
ever, the reader is referred to several excellent
reviews for a more detailed discussion of these
molecular mechanisms (Hawley, 2004; Petersen &
Shulman, 2006; Sell, Dietze-Schroeder, & Eckel,
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2006).
It is well established that increased transport and
storage of lipids into ectopic tissues plays an im-
portant role in the pathogenesis of insulin resistance
(Bonen, Dohm, & van Loon, 2006). Accumulation
of lipid within skeletal myocytes is known as
intramuscular triglyceride (IMTG), and is inversely
related to ISGD, independent of total adiposity (Pan
et al., 1997). An increase in the intracellular con-
centration of IMTG metabolites (long-chain acyl
CoA, diacylglycerol, and ceramide) has been shown
to activate a serine/threonine kinase cascade that
impairs insulin signalling at the level of IRS-1 (Yu
et al., 2002). It would appear that an increased
capacity for efficient free fatty acid utilization would
reduce the negative impact of excess lipid (Kelley &
Goodpaster, 2001), which is known to be implicated
in insulin resistance (Ruderman et al., 1998). Insulin
inhibits lypolysis and suppresses plasma free fatty
acid concentrations (Swislocki, Chen, Golay,
Chang, & Reaven, 1987). Although insulin-resistant
skeletal muscle is characterized by decreased oxida-
tive capacity and lower rates of free fatty acid
oxidation under post-absorptive conditions (Kelley,
Goodpaster, Wing, & Simoneau, 1999), increased
free fatty acid oxidation rates have recently been
reported in patients with long-term diagnosed Type-
2 diabetes. It is possible that in the absence of
compensating hyperinsulinaemia, adipose tissue in-
sulin resistance leads to a reduced suppression of
adipose tissue lipolysis, and a subsequent elevation
in free fatty acid availability and turnover, despite
elevated plasma glucose concentrations (Boon et al.,
2007).
Much like insulin-resistant individuals, endur-
ance-trained athletes, who are highly insulin sensi-
tive, are characterized by elevated levels of IMTG
(Goodpaster, He, Watkins, & Kelley, 2001). This
paradox has provided important insight into the
mechanisms associated with lipid-induced insulin
resistance. A major metabolic difference between
endurance-trained athletes and insulin-resistant in-
dividuals is the oxidative capacity of the skeletal
muscle (van Loon & Goodpaster, 2006). Endurance
exercise training increases mitochondrial density and
the proportion of IMTG in physical contact with
mitochondria, thereby enhancing free fatty acid
oxidation and preventing accumulation of the in-
sulin-desensitizing IMTG intermediates (Tarno-
polsky et al., 2007). Therefore, the ratio between
IMTG content and muscle oxidative capacity repre-
sents a far more accurate marker of insulin action
than IMTG content per se (van Loon & Goodpaster,
2006).
Exercise training is a potent stimulator of mito-
chondrial biogenesis in both healthy and insulin-
resistant individuals (Irrcher, Adhihetty, Joseph,
Ljubicic, & Hood, 2003). The energy-sensing en-
zyme, 5AMP activated protein kinase (AMPK),
plays an important role in this adaptation (Winder,
Taylor, & Thomson, 2006). AMPK is activated
during and after exercise in association with in-
creased glucose uptake, free fatty acid oxidation, and
mitochondrial biogenesis by increasing gene expres-
sion in these pathways (Winder et al., 2006). In
recent years, the peroxisome-proliferator-activated
receptor gamma coactivator 1alpha (PGC1-a) has
emerged as a master regulator of mitochondrial
biogenesis (Puigserver & Spiegelman, 2003). It has
been demonstrated that AMPK phosphorylates
PGC1-a directly, and that AMPK-activated expres-
sion of mitochondrial genes is almost entirely
dependent on the function of PGC1-a (Jager,
Handschin, St-Pierre, & Spiegelman, 2007).
Although a coordinated reduction of PGC1-a-
responsive genes has been identified in insulin-
resistant individuals, independent of fat mass or
fitness (Heilbronn et al., 2007), it is promising that
normal exercise-induced changes in AMPK have
been demonstrated in patients with Type-2 diabetes
(Musi et al., 2001). Since AMPK plays a key
signalling role in the regulation of glucose and fat
metabolism (Ruderman, Saha, Vavvas, & Witters,
1999), this may be an important mechanism through
which exercise training helps to ameliorate impaired
ISGD.
Exercise training and enhanced ISGD: The role
of weight loss
As exercise training results in increased caloric
expenditure, physical activity may facilitate weight
loss, resulting in decreased body fat, and potentially
preserved or increased muscle mass (Blair, 1993).
Individuals with insulin resistance and Type-2 dia-
betes are often overweight and up to 80% are obese

(Leibson et al., 2001), and prospective studies have
shown strong and consistent associations between
excess body fat and the incidence of Type-2 diabetes
(Lundgren et al., 1989).
It is well established that adipose tissue is not
merely a storage depot of excess energy, but an active
endocrine organ with an important role in the
regulation of many pathological processes. Adipo-
cytes express several genes encoding secreted pro-
teins termed ‘‘adipokines’’. To date, more than 50
adipokines have been identified, the most widely
investigated of which include leptin, adiponectin,
resistin, TNF-a, Interleukin-6, and more recently
retinol binding protein-4 (Kershaw & Flier, 2004).
Leptin and adiponectin differ from the other adipo-
kines in that rather than being associated with
inflammation and impairments in insulin action,
they are characterized by insulin-sensitizing and
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anti-inflammatory properties (Kershaw & Flier,
2004). Reduced levels of plasma adiponectin have
been reported in persons with obesity and Type 2
diabetes (Weyer et al., 2001). In contrast, plasma
leptin concentrations are elevated in insulin-resistant
states, implying cellular resistance to leptin rather
than deficiency of the protein (Wannamethee et al.,
2007). It was recently shown that adiponectin multi-
mers exert differential metabolic effects, with the
high-molecular-weight multimer associated with en-
hanced ISGD (Lara-Castro, Luo, Wallace, Klein, &
Garvey, 2006).
It has been shown that leptin (Minokoshi et al.,
2002) and adiponectin (Yamauchi et al., 2002)
stimulate free fatty acid oxidation in muscle by
phosphorylating AMPK. Since exercise activates
AMPK and exercise training is an effective interven-
tion for the prevention and management of insulin
resistance, it is logical to hypothesize that these
effects may be mediated through the regulation of
adipokines. However, in the absence of weight loss,
exercise training generally does not alter plasma
adiponectin levels, despite improvements in ISGD
(Yokoyama et al., 2004). Similar findings have been
reported in studies of the effects of exercise training
on other circulating adipokines known to play a role
in insulin action (Berggren, Hulver, & Houmard,
2005). In contrast, lifestyle interventions that result
in weight loss are associated with favourable changes
in circulating adipokines (Monzillo et al., 2003),
supporting the concept that weight loss and exercise
training interventions designed to improve insulin
action may function through different mechanistic
pathways.
The lipid oversupply and perturbed adipokine
function associated with obesity is known to activate
inflammatory pathways implicated in the pathogen-
esis of insulin resistance (Zick, 2003). The inhibitor
kB (IkB)/nuclear factor kB (NFkB) pathway is
Aerobic exercise vs. aetiology of insulin resistance 7
elevated in patients with Type-2 diabetes, and
exercise training was shown to reverse this abnorm-
ality in association with enhanced ISGD (Sriwijitka-
mol et al., 2006). Since the exercise intervention did
not result in weight loss, these findings support the
efficacy of exercise training per se in the reduction of
lipid-induced chronic inflammation and insulin
resistance (Pedersen, 2006).
In studies that focused on the influence of weight
loss and/or exercise training on ISGD, the improve-
ment in ISGD was greater with weight loss (induced
by caloric restriction or exercise training) than
exercise training without weight loss (Ross et al.,
2004). In these studies, ISGD was measured 96 h
after the last training session. As mentioned pre-
viously, exercise training-induced improvements in
ISGD have been shown to return to pre-training
values within a week of cessation of training. In the
exercise group designed to promote weight loss and
reductions in total, subcutaneous, and visceral
adipose tissue, the increase in ISGD was similar to
caloric restriction-induced weight loss (Ross et al.,
2004). In a similar intervention study designed to
investigate the effects of exercise training combined
with either a hypocaloric or eucaloric diet on insulin
action in older obese adults, exercise training im-
proved ISGD while the caloric restriction had little
additional benefit (O’Leary et al., 2007). Increases in
ISGD were shown to correlate with the adiponectin
multimer ratio, which suggests that exercise-induced
improvements in insulin sensitivity may, in part, be
attributed to changes in the adiponectin oligomeric
distribution. It is worth noting, however, that weight
loss occurred in both the hypocaloric and the
eucaloric diet groups, and therefore the independent
effects of exercise without the confounding influence
of reductions in fat mass were not appropriately
addressed. Results from other studies investigating
the separate influence of weight loss from exercise
training have suggested that a combination of
exercise training and weight loss is necessary to
promote increases in ISGD, and that weight loss
alone initiates only modest changes in peripheral
insulin action (Dengel, Pratley, Hagberg, Rogus, &
Goldberg, 1996). The results of these types of
studies are difficult to interpret, since dietary control
and/or exercise training was provided according to a
behavioural modification study design. In a more
recent study, participants were provided with food
during part of the intervention and supervised
during their exercise training. As such, these inves-
tigators described equivalent improvements in in-
sulin sensitivity through matched weight loss by a
25% caloric deficit (either through caloric restric-
tion-induced or exercisecaloric restriction-in-
duced) via the insulin-modified frequently sampled
intravenous glucose tolerance test (Boston et al.,
 8 S. E. Yeo & R. H. Coker
2003). Unfortunately, only 12.5% of the energy
deficit was incurred due to exercise training alone.
As a result, it is unclear whether exercise training-
induced weight loss has a more beneficial influence
on glucose metabolism in the skeletal muscle than
weight loss through caloric restriction.
Aerobic exercise, regional fat distribution, and
insulin resistance
Regional fat distribution is thought to be a more
important marker of cardiovascular and metabolic
disease risk that total body fat per se (Goodpaster
et al., 2005), and the accumulation of abdominal fat
is strongly implicated in the pathogenesis of Type-2
diabetes. This is thought to be particularly true for
individuals within normal body mass index (BMI)
ranges.
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More recently, specific analysis of abdominal fat
has resulted in some investigators proposing visceral
fat as the primary culprit of insulin resistance (Kuk
et al., 2006), while others suggest a plausible role for
abdominal subcutaneous fat (Abate, Garg, Peshock,
Stray-Gundersen, & Grundy, 1995; Goodpaster,
Thaete, Simoneau, & Kelley, 1997). More specifi-
cally, regional variations in the metabolic activity of
fat cells have been recognized (Giorgino, Laviola, &
Eriksson, 2005). It has been suggested that an
increased release of free fatty acids into the portal
vein from the more lipolytically active visceral adipose
tissue (Hoffstedt, Arner, Hellers, & Lonnqvist, 1997)
might be particularly toxic in terms of facilitating
excess endogenous glucose production (glucose Ra),
reducing hepatic extraction of insulin (Bergman
et al., 2007), and causing peripheral insulin resis-
tance (Ferrannini, Barrett, Bevilacqua, & DeFronzo,
1983).
It has been suggested that exercise training results
in a significant loss of visceral fat (Lee et al., 2005;
O’Leary et al., 2006; Ross et al., 2000), and that the
training-induced improvements in ISGD are closely
associated with the reduction of visceral fat (O’Leary
et al., 2006). Therefore, physical activity may indir-
ectly prevent or alleviate insulin resistance through
decreasing total and/or visceral obesity, even in the
absence of weight loss (Lee et al., 2005) or changes
in total body fat mass (O’Leary et al., 2006). It is
possible that the residual influence of aerobic
exercise training may rely on changes in regional
fat distribution after the more relatively acute
exercise training adaptations have returned to base-
line following cessation of training.
In addition to the detrimental influence of obesity
on peripheral insulin action, elevations in visceral
adipocyte-derived free fatty acids are linked to
accelerated gluconeogenesis and excessive glucose
Ra in individuals with impaired glucose tolerance or
Type-2 diabetes (Arner, 2002). Furthermore, this
abnormality is partially due to the reduction in the
ability of insulin to suppress lipolysis, especially in
visceral adipocytes (Arner, 2002). The efficacy of
training-induced weight loss is supported by the
results of studies that found reductions in the portal
vein concentration of free fatty acids and mesenteric
fat in rats (Nara, Takahashi, Kanda, Shimomura, &
Kobayashi, 1997). Cross-sectional studies in hu-
mans have also demonstrated greater hepatic sensi-
tivity in trained versus untrained individuals
(Rodnick, Haskell, Swislocki, Foley, & Reaven,
1987). Therefore, training-induced weight loss may
decrease the deleterious influence of excess portal
free fatty acids on insulin resistance in the liver.
Although exercise training-induced changes in he-
patic insulin sensitivity have been reported in obese
volunteers, recent studies have demonstrated no
change in hepatic insulin sensitivity in volunteers
with Type-2 diabetes (Burns et al., 2007). Therefore,
a threshold of change in visceral fat may be necessary
to induce changes in the infiltration of free fatty acids
into hepatic tissue and lessen the degree of insulin
resistance in the liver (Shojae-Moradie et al., 2007).
As such, individuals with Type-2 diabetes may
require more long-term training and/or greater
caloric expenditure (i.e. more significant weight
loss) to dampen hepatic insulin resistance.
Exercise recommendations
Given the right ‘‘dose’’, regular physical activity may
offer an effective therapeutic intervention for the
reduction of systemic insulin resistance. However,
the intensity, frequency, and duration of activity
required for improvements in insulin sensitivity
represent variables that are largely dependent upon
an individual’s fitness and degree of insulin resis-
tance. Unfortunately, physical activity and/or aerobic
exercise training guidelines for the prevention and
management of Type-2 diabetes have remained
relatively general.
For example, the Centers for Disease Control and
Prevention (CDC) and the American College of
Sports Medicine (ACSM) recommend 30 min or
more of moderate-intensity physical activity on
most, preferably all, days of the week (Pate et al.,
1995). Based on the findings of a large, 3-year
prospective, randomized clinical trial conducted by
the Diabetes Prevention Program Research Group
(2000), the American Diabetes Association endorses
these physical activity guidelines for the prevention
and management of Type-2 diabetes. A lifestyle
intervention with the goals of at least a 7% weight
loss and a minimum of 150 min of physical activity
per week reduced the incidence of Type-2
diabetes by 58% in individuals with impaired glucose

tolerance (Knowler et al., 2002). Although the
results of this and similar studies demonstrate the
efficacy of exercise and weight loss interventions for
the prevention of the onset of Type-2 diabetes, they
may be confounded by other unmeasured lifestyle
factors. In addition, the relative contributions of
increases in physical activity, reductions in caloric
intake, and reductions in body mass on improve-
ments in metabolic health cannot be determined.
The majority of individuals at risk of Type-2 diabetes
are overweight and sedentary, and therefore some
may be neither willing nor able to participate in an
aggressive exercise programme. It is important for
healthcare practitioners to suggest practical and safe
ways in which people at risk of Type-2 diabetes can
begin to incorporate physical activity into their
lifestyles, and these recommendations should be
tailored to each individual’s needs. In general,
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moderate-intensity exercise is recommended on the
basis that vigorous activity may be accompanied by
increased risk of injury and/or dropout (Diabetes
Prevention Program Research Group, 2000). How-
ever, findings from clinical intervention studies
suggest that there is no difference in injury or
dropout rates using moderate-intensity exercise
compared with more vigorous activity (Houmard
et al., 2004; O’Donovan, Kearney, Nevill, Woolf-
May, & Bird, 2005).
In training studies that have attempted to evaluate
the effects of exercise intensity on insulin sensitivity,
some suggest that high-intensity exercise training
invokes a greater change in ISGD compared with
exercise of a lower intensity (Coker et al., 2006;
DiPietro et al., 2006). In comparison, other research
findings imply that improvements in insulin sensi-
tivity with training may be independent of the
exercise intensity (Houmard et al., 2004; O’Donovan
et al., 2005).
A number of possible methodological explanations
might explain the discrepant findings. First, the
magnitude of improvements in insulin sensitivity
following a period of exercise training may be
attenuated in older compared with younger persons
(Goulet, Melancon, Aubertin-Leheudre, & Dionne,
2005). Randomized controlled studies in older
volunteers suggest that only exercise training of a
higher intensity is sufficient to enhance insulin action
(Coker et al., 2006; DiPietro et al., 2006), while
some studies in young or middle-aged people have
identified improvements with moderate-intensity
training (Houmard et al., 2004; O’Donovan et al.,
2005). It is possible that older people require a
greater exercise intensity stimulus to enhance insulin
action.
It is also worth noting that failure to control for the
total volume of exercise training or change in body
weight makes it difficult to evaluate the independent
Aerobic exercise vs. aetiology of insulin resistance 9
effects of exercise intensity on insulin sensitivity.
Houmard and colleagues (2004) used a randomized
design controlled for exercise volume (1200 kcal per
week) to compare the independent effects of moder-
ate-intensity (40
55% VO2peak) exercise training and
high-intensity (65
80% VO2peak) exercise training on
insulin sensitivity, as assessed by the intravenous
glucose tolerance test, in middle-aged, overweight/
obese individuals who completed a 6-month training
programme. At first glance, it is somewhat surprising
that moderate-intensity exercise training was asso-
ciated with greater increases in insulin sensitivity
(88%) than high-intensity training (38%). The
authors attributed the favourable benefits of the
moderate-intensity training to the longer weekly
training duration and concluded that total exercise
duration should be considered when designing an
exercise programme. However, despite the control of
caloric expenditure, and the provision of exercise
supervision, there was a discrepancy relative to body
weight. For example, Houmard et al. (2004) point
out that moderate-intensity exercise resulted in
weight loss, whereas there was no change in body
weight with high-intensity exercise training. This is
important since weight loss and exercise training are
likely to have independent effects on insulin action,
and thus the weight loss in the moderate-intensity
training group may explain the greater improvements
in insulin sensitivity. While the authors report no
associations between insulin sensitivity and body
weight, it is still possible that unmeasured changes
in the distribution of body fat could explain the
findings.
In a similar study, O’Donovan and colleagues
(2005) investigated the independent effects of ex-
ercise intensity on insulin resistance in overweight
men who completed a 24-week exercise training
programme (1200 kcal per week). In contrast to the
findings of Houmard et al. (2004), the improvements
in insulin action were independent of exercise
intensity. Again, however, changes in weight and
body composition may have confounded the results,
and prevented the true independent effects of
exercise intensity from being elucidated. Indeed,
while exercise-induced changes in weight did not
predict alterations in insulin resistance, changes in
waist girth predicted much of the variation in insulin
sensitivity. Given the established relationships be-
tween visceral obesity and insulin resistance (Berg-
man et al., 2007), these findings are not surprising.
In recent studies of older individuals that ade-
quately controlled for caloric expenditure, and which
did not result in weight or fat loss, high-intensity
exercise was shown to have greater benefits than
exercise of lower intensity (Coker et al., 2006;
DiPietro et al., 2006). DiPietro and colleagues
(2006) recently examined the influence of exercise
 10 S. E. Yeo & R. H. Coker
intensity on insulin sensitivity in overweight, older
women who were randomized to high-intensity
(80% VO2peak), moderate-intensity (65% VO2peak),
or a low-intensity (stretching) placebo control group.
Participants in the high- and moderate-intensity
groups completed a 9-month supervised exercise
training protocol designed to expend 1200 kcal per
week. While a dose
response relationship between
exercise intensity and increases in ISGD were
evident (i.e. 21%, 18%, and 8% for high-, moder-
ate-, and low-intensity training prospectively),
favourable changes were only significant in the
high-intensity exercise group. In addition, improve-
ments in insulin-stimulated suppression of adipose
tissue lipolysis were only identified with high-inten-
sity exercise training. Elevated catecholamine release
during and after high-intensity exercise causes an
increase in whole-body lipolysis (Mora-Rodriguez &
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Coyle, 2000) and may help to explain the more
durable effects of high-intensity exercise training on
elevated free fatty acid turnover, fat mass reduction,
and enhanced ISGD. However, neither body mass
nor body composition was altered in any of the three
groups, which suggests that improvements in insulin
sensitivity were likely to result from the exercise
training stimulus per se. Consistent with the findings
of DiPietro et al. (2006), we conducted a 12-week
exercise training study in obese, elderly men and
women, which did not result in weight or body fat
loss. When controlled for caloric expenditure (1000
kcal per week), only high-intensity (75% VO2peak),
not moderate-intensity (50% VO2peak), exercise
training was associated with improvements in
ISGD. When ISGD was partitioned into that from
oxidative and non-oxidative sources, increases in
ISGD with high-intensity training were completely
reliant on improvements in non-oxidative glucose
disposal (Coker et al., 2006). Non-oxidative glucose
disposal is largely due to glycogen synthesis and is
directly related to the fractional activity of glycogen
synthase in skeletal muscle (Ebeling et al., 1993).
High-intensity aerobic exercise relies on muscle
glycogen to a greater extent than exercise of lower
intensity (Romijn et al., 1993), and acute improve-
ments in insulin action may be dependent upon the
depletion of muscle glycogen stores (Richter et al.,
1984). Therefore, despite adjustment of the duration
of exercise to achieve a similar amount of energy
expenditure during moderate-intensity exercise com-
pared with high-intensity exercise, the relative con-
tribution of muscle glycogen utilization to the total
energy production was different. Hence, the greater
glycogen stores following moderate-intensity exer-
cise may limit non-oxidative glucose disposal. We
have also shown that an ad libitum, high carbohy-
drate diet alone or consumed in conjunction with
high-intensity exercise training results in similar
significant improvements in ISGD (Hays et al.,
2006b). In these studies, muscle glycogen stores
doubled following the exercise and dietary interven-
tion, potentially limiting non-oxidative glucose dis-
posal. Therefore, the improvement in ISGD that
occurred with high-intensity exercise may be related
to greater muscle glycogen utilization during ex-
ercise, even when ISGD was assessed 72 h after the
last exercise bout, potentially minimizing any acute
affects from the final exercise session.
Perhaps more important than differences in ex-
ercise intensity, elevations in caloric expenditure are
thought to exert a primary influence on improve-
ments in obesity-related complications (Despres,
1997). Physical activity expressed as energy ex-
pended per week is positively related to decrements
in total abdominal fat (Ross & Janssen, 2001), and
inversely related to the development of Type-2
diabetes (Helmrich, Ragland, & Paffenbarger,
1994). Moderate-intensity exercise may therefore
be an effective strategy, if it is performed frequently,
and for long enough duration to induce significant
caloric deficit. In addition, more aggressive exercise
training programmes that include weight loss may be
required to prevent and manage insulin resistance,
especially in those at high risk of Type-2 diabetes
(Ross & Janssen, 2001).
It should be realized that when evaluating the
results of studies that vary in terms of intensity,
volume, and mode of exercise training, caution
should be taken when making comparisons between
studies using indirect methods of insulin sensitivity
compared with the direct method of determining
ISGD via the euglyceamic
hyperinsulinaemic clamp
(Andres, Swerdolff, Pozefsky, & Coleman, 1965).
This is largely due to the demonstration of poor
reproducibility of results, even when comparing the
results of indirect versus direct methods in the same
individual (Andres et al., 1965). Therefore, these
methodological discrepancies may be responsible in
part for different conclusions regarding these ex-
ercise training studies, and one should be aware that
drawing equivocal conclusions from studies using
different protocols/techniques may be flawed due to
inconsistencies (Andres et al., 1965) or larger varia-
tions in the data produced from indirect assessment
(Hays et al., 2006a).
Conclusions
It is now widely accepted that regular physical
exercise may offer an effective therapeutic interven-
tion to reduce the risk of Type-2 diabetes in persons
with varying degrees of insulin resistance. Exercise
training programmes that are designed specifically to
increase caloric expenditure and promote weight loss
appear to be the most effective, and seem to provide

longer-lasting benefits than short-term training pro-
grammes. Although somewhat beneficial, the short-
term improvements in insulin sensitivity through
exercise training without weight loss appear to
dissipate rather rapidly upon cessation of exercise,
and may be more related to the acute changes in fuel
utilization during exercise rather than therapeutic
modulation of insulin signalling. Therefore, exercise
training programmes should be progressive so that
the caloric expenditure provides the therapeutic
benefits of exercise training combined with the loss
of body fat (Ross, Freeman, & Janssen, 2000). In
addition to progressive application of increased
caloric expenditure, dietary reduction of caloric
intake combined with exercise training may also be
an effective, efficacious option for the treatment of
insulin resistance (Larson-Meyer et al., 2006).
Downloaded By: [European College of Sport Science] At: 08:49 2 August 2010
Acknowledgements
This research was supported by NIH grants KO1
DK 64716-01 (R.H.C.) and AHA grant SDA
0335172N (R.H.C.). We also acknowledge the
support of the University of Arkansas for Medical
Sciences General Clinical Research Center funded
through grant M01 RR14288.
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