Effects of exercise on inflammation

markers in type 2 diabetic subjects

E. Hopps, B. Canino & G. Caimi

Acta Diabetologica
ISSN 0940-5429
Volume 48
Number 3
Acta Diabetol (2011) 48:183-189
DOI 10.1007/s00592-011-0278-9

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Acta Diabetol (2011) 48:183189
DOI 10.1007/s00592-011-0278-9

REVIEW ARTICLE

Effects of exercise on inflammation markers in type 2 diabetic

subjects
E. Hopps B. Canino G. Caimi

Received: 5 February 2011 / Accepted: 10 March 2011 / Published online: 24 March 2011
Springer-Verlag 2011

Abstract Endothelial dysfunction and plasma markers of

inflammation are significantly increased in type 2 diabetics.
Several proinflammatory cytokines, acute-phase proteins,
and cell adhesion molecules, such as C-reactive protein
(CRP), interleukines (IL), and tumor necrosis factor alpha
(TNF-a), seem to play a role in the low-grade systemic
inflammation observed in these subjects. Lifestyle changes
are necessary to prevent atherosclerosis and cardiovascular
events. Physical exercise is known to reduce markers of
inflammation by decreasing adipocytokine production and
cytokine release from skeletal muscles, endothelial cells,
and immune system and also improving antioxidant status.
In type 2 diabetics, aerobic and resistance training have
different effects on cytokine levels, and the differences in
the modalities of exercise (type, duration, and intensity)
and especially in the examined population could produce
different results. Recent research showed that combined
exercise has greater anti-inflammatory effects than aerobic
or resistance exercise alone causing a deepest decrease in
CRP, IL-6, IL-1b, TNF-a, leptin, and resistin and a higher
increase in anti-inflammatory cytokines such as IL-4,
IL-10, and adiponectin.
Keywords Type 2 diabetes mellitus Aerobic exercise
Resistance exercise Inflammation

E. Hopps (&) B. Canino G. Caimi

Dipartimento di Medicina Interna, Malattie Cardiovascolari
e Nefrourologiche, Universita` degli Studi di Palermo,
Via del Vespro, 129, 90127 Palermo, Italy
e-mail: euhopps@libero.it

Introduction
Cardiovascular disease is the most important cause for
morbidity and mortality in type 2 diabetic subjects.
Endothelial dysfunction is the primum movens in the
pathogenesis of atherosclerosis. Inflammation has been
shown to contribute to endothelial dysfunction: Leukocyte
infiltration into the vascular wall seems to be involved in
all the stages of the process, and chemokines, such as
interleukin-8 (IL-8) and monocyte chemoattractant protein1 (MCP-1), play a role by attracting mononuclear cells into
arterial wall. Moreover, elevated cytokine and C-reactive
protein (CRP) levels are correlated with the increased risk
of developing cardiovascular diseases and diabetes mellitus
[1]. Low-grade systemic inflammation, which is an independent predictor of all-cause mortality, is often associated
with diabetes mellitus and obesity. In obesity and type 2
diabetes mellitus, this low-grade inflammation state reflects
the activation of innate immunity with the implication of
metabolic, environmental, and genetic factors [2]. Physical
activity is associated with reduced risk of cardiovascular
disease, cardiovascular death, and total mortality in subjects with type 2 diabetes mellitus. The beneficial effects of
exercise on reduced cardiovascular risk could at least partly
be mediated by improved markers of inflammation. The
aim of this paper has been to review the literature data
concerning the impact of exercise intervention on inflammatory parameters, subdivided into myokines, adipokines,
cytokines, and acute-phase proteins, in type 2 diabetic
subjects and also to clarify the effects of different types of
exercise to the purpose of suggesting more specific lifestyle
recommendations for these kind of subjects.
We carried out a search on PubMed using the following
terms: diabetes mellitusexerciseinflammation markers, for literature published up to January 2011. At this

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184

regard, we found 62 abstracts and 56 manuscripts. The

cited papers were selected on the basis of their relevance
with the topic of this review.

Type 2 diabetes mellitus and inflammation

Atherosclerotic plaques in subjects with type 2 diabetes
mellitus (T2D) seem to have more inflammatory properties
and a worse cardiovascular outcome than plaques observed
in non-diabetic subjects [3]. Several data indicated that
CRP and proinflammatory cytokines, including IL-6 and
tumor necrosis factor alpha (TNF-a), are increased in
subjects with T2D [4]. Elevated levels of CRP and IL-6
predict insulin resistance and endothelial dysfunction and
subsequently development of type 2 diabetes mellitus and
atherosclerosis [5]. CRP is considered the link between
inflammation and atherosclerosis, being a predictor of
cardiovascular events and of the outcome of acute coronary
syndromes [6]. T2D subjects can be subdivided into low,
intermediate, and high risks for cardiovascular disease
based on hsCRP (high-sensitivity C-reactive protein) levels
[7]. Elevated levels of CRP and fibrinogen and reduced
level of adiponectin may be used for early diagnosis of
T2D and can predict chronic diabetic complications [8].
The elevation of proinflammatory molecules concentrations in T2D subjects might probably be caused by
hyperglycemia and oxidative stress. Hyperglycemia seems
to activate the immune and macrophage-monocyte systems
and to stimulate the production of cytokines and acutephase proteins (IL-6 is the main stimulus to CRP production in the liver), which are also involved in the decreased
endothelial-dependent vasodilation [9]. Elevated levels of
HbA1c are related to an impaired nitric oxide-mediated
vasodilation by a mechanism involving superoxide anion
but not cyclooxygenase derivatives [9]. In addition,
hyperglycemia induces oxidative stress, that is responsible
for the activation of nuclear factor-kB, that increases serum
levels of circulating proinflammatory cytokines [5]. A
positive correlation between HbA1c and nitrotyrosine was
observed in diabetics, even in subjects with well-controlled
type 2 diabetes [10]. In these subjects, inflammation was
more related to abdominal obesity than to glycaemic control [10]. Hansen et al. [11] hypothesized that altered
inflammatory markers and plasma adipokines are related to
the obese state and are not prevalent in non-obese type 2
diabetic subjects. They observed that hsCRP, IL-6, and
leptin levels were elevated in obese T2D subjects, as
opposed to healthy, normoglycemic controls. No significant differences were found between non-obese type 2
diabetics and healthy controls. So, in their opinion, altered
plasma cytokine levels are more related to adipose tissue
mass than to the presence or absence of diabetes mellitus or

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to the glycometabolic control. In a large group of subjects

with type 2 diabetes, BMI was associated with CRP and IL6 levels. Visceral, but not subcutaneous, adipose tissue was
related to the markers of systemic inflammation that are
associated with vascular wall remodelling. So, adipose
tissue distribution results a specific determinant of systemic
inflammation also in type 2 diabetes mellitus [12]. There is
also a positive correlation between waist circumference
and hsCRP and between hsCRP and IL-6 [10]. Nayak et al.
[13] observed that adiponectin levels were significantly
lower in diabetics and negatively correlated with BMI
(body mass index) adjusting for age, diabetic status, and
gender. However, there was no significant correlation
between adiponectin and inflammatory markers.
Other authors showed that hsCRP levels were significantly higher in diabetic men and women as compared to
the non-diabetic controls and positively associated with
T2D, even after adjusting for obesity markers [4, 14].
Several studies have shown that levels of physical activity
and cardiorespiratory fitness are inversely correlated with
CRP and that regular exercise reduces plasma levels of
CRP and other inflammatory markers [1517]. In brief, all
these data underline how in diabetes mellitus a systemic
inflammation is evident.

Exercise in type 2 diabetes mellitus: anti-inflammatory

effects
The American Diabetes Association [18] encourages individuals with T2D to perform a regular exercise training
three times a week targeting all major muscle groups. The
same suggestion seems to emerge from the review of other
authors [19].
As the U.S. Department of Health and Human Services
Physical Activity suggests for healthy subjects, people with
diabetes should perform at least 150 min/week of moderate-intensity aerobic physical activity and, in the absence
of contraindications, they should be encouraged to perform
resistance training three times per week [18]. A warm-up
session consisting of 510 min of aerobic activity (walking, cycling) at a low intensity level is recommended to
prepare the skeletal muscles, heart, and lungs for a progressive increase in exercise intensity, considering precautionary measures for exercises involving the feet.
Individuals with peripheral neuropathy should wear proper
footwear and examine their feet daily to detect lesions
early [18]. High-intensity resistance exercise using weights
may be contraindicated for older individuals, while a
moderate-intensity weight training program that utilize
light weights and high repetitions can be used for maintaining or enhancing body strength in all subjects with
diabetes mellitus [18]. In subjects with diabetic

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Acta Diabetol (2011) 48:183189

retinopathy, strenuous aerobic or resistance exercise may

be contraindicated because of the risk of vitreous hemorrhage or retinal detachment [18].
Ribeiro et al. [20] in a review describe an inverse
association between inflammation markers and physical
activity: Physical exercise reduces markers of inflammation promoting the reduction in visceral adipose tissue and
the consequent decrease in adipocytokine production and
also attenuating cytokine release from skeletal muscles,
endothelial cells, and immune system. In addition, exercise
training improves antioxidant defences, and the nitric oxide
bioavaibility favouring the regenerative capacity of endothelium; the reduced oxidative stress may have an antiinflammatory effect by limiting monocyte activation [20].
Myokines
Skeletal muscle can be considered as an endocrine organ;
its contraction may stimulate production and release of
cytokines, which can influence metabolism and modify
cytokine production in other tissue and organs [21]. Some
cytokines (myokines), such as IL-6, are released by
muscle in response to endurance exercise, but the IL-6
produced by myocites has anti-inflammatory effects as
opposed to IL-6 secreted by adipose tissue [22]. IL-6
derived from muscles in fact promotes the release of other
anti-inflammatory cytokines, such as IL-10 and IL-1ra (IL1 receptor antagonist), and inhibits IL-1b and TNF-a production. IL-1ra binds to IL-1 receptors but does not induce
any intracellular response. IL-1b does not increase neither
after endurance exercise nor after resistance training [23,
24]. An imbalance between IL-1ra and IL-1b seems to
predispose to metabolic and inflammatory diseases such as
diabetes mellitus and rheumatoid arthritis [25]. TNF-a
levels increase only during a very strenuous exercise
(marathon running), in response to muscle damage [26].
Modality, duration, and especially intensity of exercise
determine the increase in plasma IL-6 that is correlated
with the muscle mass involved in contractile activity [26].
IL-6 produced by muscles during physical activity raises
hepatic glucose production and lipolysis in the adipose
tissue [26]. It was demonstrated that glucose ingestion
during exercise reduces IL-6 production by muscle [26]
and so it was supposed that IL-6 is released because of the
reduction in glycogen levels that occurs during endurance
exercise and the consequent adrenergic stimulation of IL-6
gene transcription via protein kinase A activation [21, 26].
IL-8 is a chemokine that acts as an angiogenic factor; it
increases in response to vigorous exercise such as running,
which involves eccentric muscle contractions, and in
response to concentric exercise, such as bicycle ergometry
or rowing [26]. IL-15 levels are elevated in human skeletal
muscle following a bout of strength training; it has been

185

identified as an anabolic factor, which is highly expressed

in skeletal muscle, stimulating myogenic differentiation. It
seems to reduce white adipose tissue mass, and it was also
suggested that IL-15 plays a role in muscle-adipose tissue
interaction modulating body composition and insulin sensitivity [26].
IL-4, IL-13, IL-4 ra, and IL-13 ra are expressed in
human skeletal muscle in vivo and are up-regulated after
strength training in athletes [27]. After 6 weeks of resistance training, their mRNA expression increases in healthy
active individuals but their protein levels do not raise [27].
These cytokines might be involved in muscle hypertrophy;
IL-4 especially can promote muscle regeneration, which
involves de novo myofiber formation [27].
Gordon et al. [28] examined in muscles of older
(67 7 years) diabetic subjects the expression of genes
encoding TNF-a, IL-1b, and transforming growth factor-b1
(TGF-b1) after 16 weeks of resistance training observing
that this exercise increased these cytokine transcript levels
and promotes muscle fiber hypertrophy. Other authors
observed an increase in IL-6 and MCP-1 expression in
muscle samples from type 2 diabetic and obese subjects
after a bout of moderate-intensity aerobic exercise (cycle).
The expression of these cytokines is regulated by nuclear
factor-kB, whose activity is higher in diabetic subjects even
in basal condition [29]. From these data, we suppose that
the long-term resistance training induces muscle injury and
a consequent elevation in inflammation markers in older
diabetic patients, while a session of moderate-intensity
aerobic exercise promotes the production of muscular IL-6
with anti-inflammatory properties.
Adipokines
Adipose tissue produces cytokines that act as pro-inflammatory mediator activating the production and the release
of macrophage cytokines [1]. These cytokines stimulate
hepatic production of acute-phase protein inducing a
chronic systemic inflammatory response [31]. More than
50 adipokines have been identified including leptin,
adiponectin, resistin, IL-6, plasminogen activator inhibitor1 (PAI-1), retinol binding protein 4 (RBP4), TNF-a, and
visfatin [30].
Leptin/leptin receptors have pro-inflammatory and
immunomodulatory effects; leptin interferes with neutrophil chemotaxis and phagocytic function, stimulates the
production of pro-inflammatory cytokines from cultured
monocytes, and enhances the production of Th1-type
cytokines [30]. On the contrary, adiponectin reduces
macrophages TNF-a release modulating inflammatory
response [30]. Resistin and visfatin induce chemotaxis and
secretion of chemokines, CRP, TNF-a, IL-12, and IL-6 [30,
31]. RBP4 expression is related to inflammatory markers in

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obese subjects [30]. Aerobic exercise of moderate intensity

and regularly performed for 10 weeks improves insulin
sensitivity, increases adiponectin levels, and decreases
RBP4 concentrations [32]. RBP4 reduction is more marked
in older than in young diabetic subjects, and this is probably related to the basal values of RBP4 that are higher in
older patients [32]. Also, a 12-week resistance training of
moderate intensity reduces RBP4 levels in type 2 diabetics
[33]. Improvements in adiponectin concentrations have
been reported after aerobic exercise and resistance training.
There are conflicting data on the influence of resistance
training on adiponectin concentrations; while some authors
did not observe any change [3438], others have reported
its increase [6, 39]. The results quoted in a systematic
review on adiponectin underlined that both aerobic and
resistance training improve its levels in about one-third of
the examined randomized controlled trial, including sedentary, obese, and type 2 diabetic subjects [40]. An acute
bout of exercise does not produce any effects on adiponectin levels in subjects with impaired glucose tolerance
(IGT) or T2D, suggesting that changes in body composition are necessary for increasing adiponectin concentrations [40]; moderate to high-intensity exercise programs
seem to be most efficacious [40]. However, it has been
demonstrated by Balducci et al. [6] that reduction in
cytokine and adipokine plasma levels in subjects with
diabetes mellitus or metabolic syndrome is independent of
weight loss, but is correlated with the type of exercise
performed. These authors observed in fact that proinflammatory cytokines, leptin, and resistin decrease more in
subjects trained for 12 months with combined aerobic and
resistance training of high intensity than in subjects trained
with aerobic exercise only. So, endurance exercise is recommended to increase aerobic capacity and cardiorespiratory fitness combined with moderate to high-intensity
resistance training.
Cytokines and acute-phase proteins
Although the results of some studies [41, 42] suggest
that physical activity is not associated with a reduction
in inflammation markers, data obtained from other
research support instead that exercise training reduces
inflammation indicators [43, 44] and demonstrate the
influence of exercise in mitigating the risks of obesity,
T2D, and cardiovascular diseases. An immuno-modulatory effect of regular exercise, and in particular
resistance training, has been suggested by some authors
[46, 47]. Differences in the type, duration, and intensity
of training and more likely in the examined population
(patients with IGT or T2D, older or not, overweight or
obese, with or without complications) could explain the
contrasting results.

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When subjects with metabolic syndrome, very often

diabetic, physically inactive, and with central obesity,
perform physical activity they show a reduction in MCP-1
and IL-8 [48].
IL-18, which is associated with multiple components of
the metabolic syndrome, decreases after 12 weeks of
exercise, and its reduction is associated with the
improvement in many factors of the syndrome [49]. Subjects with IGT or T2D treated with regular physical training showed an improvement in body fat, fitness level, and
HOMA-IR, associated with an improvement in CRP and
IL-6 plasma concentrations, especially in the long term [50,
51]. In particular, a trial was carried out on IGT and T2D
subjects trained three times a week with a 60-min program
consisting of 20 min of warming and cool-down periods,
20 min of running or biking, and 20 min of power training
[50], and the other one included endurance exercise to
increase aerobic capacity and moderate-intensity resistance
training sessions to improve the functional capacity and
strength of muscles too [51].
Adiponectin and IL-10, anti-inflammatory cytokines, are
inversely correlated with fasting plasma glucose levels
[50].
Overweight individuals with T2D, without vascular
complications, randomly assigned to a 6-month aerobic
exercise program (four times/week, 4560 min/session)
shown a decrease in hsCRP and IL-18 levels, an increase in
anti-inflammatory cytokine, such as IL-10, and an
improvement of the IL-18/IL-10 ratio [45]. On the contrary, in older obese diabetics, a 6-month aerobic training
program without a concomitant weight-loss diet decreased
plasma biomarkers of endothelial dysfunction, such as
P-selectin and other adhesion molecules, but not hsCRP
and soluble TNF-a receptor concentrations [51]. In this
case, the unchanged levels of inflammation indicators, as
well as that of body weight and waist circumference, were
associated with the absence of a significant variation in
visceral fat [52].
After 4 weeks of aerobic training, even if endothelial
function remained unchanged, fasting glucose, HbA1c, and
hsCRP serum levels decreased, coming back at basal levels
in 6 months [44]. At the same time, muscle expression of
adiponectin receptor, NADPH oxidase subunits, and
PPARc increased after 4 weeks of exercise and decreased
after 6 months, suggesting an adaptation to chronic exercise training [44]. The decrease in NADPH oxidase
expression is an evidence of the improvement in oxidative
stress with an intervention focused on exercise training.
Regarding PPARc, it is still unknown whether its increase
or decrease after exercise is favorable.
Long-term resistance training improves CRP but not IL6 concentrations; CRP seems to decrease with this kind of
exercise especially in women, obese individuals or the

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Acta Diabetol (2011) 48:183189
Table 1 Effects of different
modalities of exercise on main
cytokines and acute-phase
protein in type 2 diabetics

Combined aerobic plus

resistance exercise shows a
greater anti-inflammatory effect
CRP C-reactive protein, IL
interleukin, TNFa tumor
necrosis factor alpha, RBP4
retinol-binding protein 4

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Aerobic
training

Resistance
training

CRP

IL-6

IL-1b

TNF-a

IL-10

IL-4

Resistin

Leptin

RBP4

Adiponectin

elderly [53]. Regarding TNF-a, high-intensity resistance

training seems to reduce its concentrations, even when fat
mass is unchanged [54], whereas it is not modified by
aerobic exercise [45].
The paper of Balducci et al. [6] demonstrates that
hsCRP, IL-6, IL-1b, and TNF-a reduction is more evident when subjects are trained for 12 months with
combined aerobic and resistance training of high intensity compared with subjects trained with aerobic exercise only and, on the contrary, that anti-inflammatory
cytokines (IL-4 and IL-10) increase more in the mixed
exercise group.
So, anti-inflammatory effects are related to the exercise
modality and intensity and also to its duration: long-term
aerobic plus resistance exercise are much more effective
than aerobic training in reducing biomarkers of inflammation, despite a comparable caloric expenditure.

Conclusion
As it is known, subjects with T2D have an increased
risk for atherosclerosis. Low-grade chronic systemic
inflammation is considered as a link between atherosclerosis and T2D and could therefore represent the
common pathogenic factor in the development of these
diseases. Aerobic and resistance training, and especially
combined exercise, improve inflammation biomarkers
(Table 1) and so may reduce the risk of cardiovascular
disease, cardiovascular death, and total mortality in
these subjects. Long-term high-intensity training, preferably performed daily, is necessary to obtain a significant anti-inflammatory effect. In light of all these data,
we retain that further investigation will be needed to
clarify the role of exercise on inflammation biomarkers
and especially the role of these biomarkers on the cardiovascular implications.

Combined
training

References
[6, 42, 43, 52]
[6, 47, 48]
[6, 22, 23]
[6, 43, 53]
[6, 43]
[6, 26]

[6]

[6]

Unavailable data

[31, 32]

[6, 37, 38]

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