DOI: 10.1111/eci.

12468

ORIGINAL ARTICLE

Habitual physical activity is associated with circulating

irisin in healthy controls but not in subjects with
diabetes mellitus type 2
Nasser M. Al-Daghri*,†, Majed S. Alokail*,†, Shakilur Rahman*, Osama E. Amer*, Omar S. Al-Attas*,†, Hanan
Alfawaz†‡, Gyanendra Tripathi§, Shaun Sabico*, George P. Chrousos¶, Philip G. McTernan§ and Milan K. Piya§
*
Biomarkers Research Program, Biochemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia,
†
Prince Mutaib Chair for Biomarkers of Osteoporosis, Biochemistry Department, College of Science, King Saud University,
Riyadh, Saudi Arabia, ‡Department of Food Science and Nutrition, College of Food Science and Agriculture, King Saud
University, Riyadh, Saudi Arabia, §Division of Translational and Systems Medicine, Warwick Medical School, University of
Warwick, Coventry, UK, ¶First Department of Pediatrics, Athens University Medical School, Athens, Greece

ABSTRACT
Background Irisin, a novel myokine, has been shown to increase following vigorous exercise, with studies
suggesting that it mediates some of the beneficial effects of exercise. Irisin might play a role in ‘browning’ of
white adipocytes, thus increasing energy expenditure. The role of irisin in exercise and energy expenditure in
subjects with diabetes mellitus type 2 (DMT2) remains largely unknown. We aimed to investigate the associ-
ation between circulating irisin and habitual physical activity in subjects with and without DMT2.
Material and methods In this cross-sectional study, 164 Saudi adults: 81 non-DMT2 controls [age:
(mean  SD) 51
6  10
9; BMI: 29
6  4
3 kg/m2] and 83 DMT2 subjects [age: 54
3  10
3 year; BMI:
29
4  4
7 kg/m2] were studied. Anthropometric and fasting serum biochemical data were collected. Circu-
lating irisin was measured using an enzyme-linked immunosorbent assay (ELISA). Frequency intensity time (FIT)
index was used to assess the level of habitual physical activity.
Results We observed significantly higher levels of irisin in DMT2 subjects than in controls (P < 0
001). FIT index
was positively associated (r = 0
20, P = 0
03) with circulating irisin in controls only. Additionally, irisin levels
were significantly higher in tertile 3 (0
75  0
07 lg/mL) than tertile 1 (0
49  0
06 lg/mL) of the FIT index in
healthy controls, whilst no such relation with physical activity was observed in DMT2 subjects.
Conclusion This cross-sectional study has shown a weak association of irisin with physical activity levels in
healthy controls but not in DMT2 subjects, suggesting the possibility of discordant regulation in the condition of
DMT2.
Keywords Diabetes, frequency intensity time index, irisin, physical activity.
Eur J Clin Invest 2015; 45 (8): 775–781

fold increase in UCP-1 and resulted in increased energy

Introduction
The hormone irisin from the proteolytic cleavage of fibronectin
type III domain-containing 5 (FNDC5) has been observed to
improve glucose homoeostasis and increase energy expendi-
ture in humans [1–4]. Irisin can induce a change in character-
istics of white adipocytes into ‘beige’ or ‘brite’ adipocytes,
referred to as ‘browning’ [1]. This change includes the activa-
tion of uncoupling protein 1 (UCP-1) in beige adipocytes,
leading to increased respiration and energy expenditure [1,3]. It
has been observed that even moderate increases in circulating
irisin levels in mice fed a high fat diet stimulated a 10- to 20-
expenditure and improved glucose tolerance [1].
The health benefits of exercise have been widely accepted [5].
Regular physical activity is known to promote systemic
metabolism and exert multiple beneficial effects including the
prevention and treatment of hypertension, coronary heart dis-
ease, obesity and diabetes mellitus type 2 (DMT2) [6–8]. It has
been also recognized that a minimum amount of habitual
physical activity is desirable to reduce mortality risk [9]. Recent
reports indicate that the beneficial effects of exercise maybe
partially mediated by irisin, which increases after acute exercise
training [10–13]. In contrast, there is conflicting evidence on the

European Journal of Clinical Investigation Vol 45 775

 N. M. AL-DAGHRI ET AL. www.ejci-online.com

changes in circulating irisin with longer-term physical activity

or exercise training [14–19]. Some reports indicate that the
Anthropometrics and blood collection
Participants were advised to visit to their respective PHCCs in
metabolic state of an individual may also influence the regu-
the morning after an overnight fast (> 10 h) and avoid vigorous
lation of circulating irisin [10,15,20–26].
physical activity on the preceding day. Anthropometric data
Therefore, in this study, we aimed to evaluate the impact of
collected include height (cm); weight (kg); waist and hip cir-
habitual physical activity on circulating irisin levels in healthy
cumferences (cm); sagittal abdominal diameter (SAD) (cm);
controls and DMT2 subjects in an adult Saudi population.
and systolic and diastolic blood pressures (mm Hg) (average of
Saudi subjects are of particular interest due to their lower
two readings 15 min apart). Body mass index (BMI) was cal-
physical activity levels and higher risk for metabolic dysfunc-
culated as the weight in kilogram divided by the square of the
tion including DMT2 compared to white Caucasians, where
height in metres. Lean body mass (LBM), which is fat-free
most of the studies on irisin have been conducted [27–29].
weight from the total body weight, was calculated using the
Hume’s mathematical formula [34]. For men,
Materials and methods
LBM = (0
32810*W) + (0
33929*H) – 29
5336 and for
women, LBM = (0
29569*W) + (0
41813*H) – 43
2933, where
Subjects and experimental design
‘W’ is body weight in kilograms, and ‘H’ is body height in
A total of 164 Saudi subjects (77 men; 87 women), aged 30–
centimetres. Fasting blood samples were drawn and centri-
75 years, were selected from different Primary Health Care
fuged. The collected sera were then transferred to a prelabelled
Centers (PHCCs) in Riyadh, KSA. These individuals were part
tube, stored in ice and delivered to the Biomarkers Research
of the Biomarker Screening in Riyadh Project (RIYADH
Program (BRP) at King Saud University, Riyadh, KSA, for
COHORT) [27]. All participants provided written and informed
immediate storage at 80 °C until analysis.
consent prior to inclusion. Ethical approval was granted by the
Ethics Committee of the College of Science Research Center,
King Saud University, Riyadh, Kingdom of Saudi Arabia
Biochemical analysis
Fasting glucose (FG) and lipid profile were measured using a
(KSA). Participants completed a questionnaire about their
chemical analyzer (Konelab 20XTi; Thermo fisher Scientific,
habitual physical activity, demographic information, general
Vantaa, Finland). Irisin was measured using an enzyme-linked
health status and past medical history. Subjects were subdi-
immunosorbent assay (ELISA) (Phoenix Pharmaceuticals Inc,
vided into non-DMT2 controls (n = 81) and those having DMT2
Burlingame, CA, USA) as previously reported by our group
(n = 83). Patients with fasting blood glucose (FBG)
[25,35,36] with an intra-assay variability of < 10% and interas-
≥ 7
0 mmol/L and/or taking oral hypoglycaemic drugs were
say variation of < 15%. All fasting samples fell within the
considered to have DMT2.
detection range.
Assessment of habitual physical activity
Each subject’s habitual physical activity was assessed based on
Statistical analyses
Sample size calculation was performed using G*Power version
a standardized questionnaire using FIT (frequency intensity
3.0.10. Given a = 0
05, b = 0
95 and an effect size of one calcu-
time) index [30–33]. This index requires that points are allo-
lated from the actual mean and standard deviation (two-tailed)
cated depending on the frequency, intensity and time spent
differences of irisin levels obtained from both groups (control
performing physical activity per week. Frequency and intensity
and DMT2), a sample size of 27 per group has a power of 0
95,
of physical activity were assessed using a 1–5 scale and time
and the actual sample size (81 controls and 83 DMT2) has a
spent was measured on a 1–4 scale, with the FIT total being the
power of 0
998.
product of the three components, scores ranging from 1 (min-
Data analyses were carried out using the Statistical Package
imum activity) to 100 (training at a high intensity every day of
for Social Sciences software (SPSS 16
0; SPSS Inc, Chicago, IL,
the week). Frequency was the number of times spent exercising
USA). Data were expressed as mean  standard deviation.
per week, and intensity ranged from ‘light aerobic activity such
Kolmogorov–Smirnov test was performed to test continuous
as normal walking’ to ‘high-intensity activities such as running,
variables for normality. All non-Gaussian parameters (includ-
high impact aerobics and distance cycling’. In essence, the scale
ing irisin) were logarithmically transformed or square-root-
established that the higher the score, the more physically active
transformed to normalize prior to correlations and parametric
the person. The product of these three components (frequency,
analyses. Independent Student’s t-test was employed to com-
intensity and time) indicates the level of habitual physical
pare the means between the groups of normally distributed
activity. Thus, FIT index was calculated as follows: FIT
data. Pearson’s correlations and regression analyses between
index = (points for frequency)*(points for intensity)*(points for
serum irisin and the anthropometric and metabolic parameters
time) [30–33].

776 ª 2015 Stichting European Society for Clinical Investigation Journal Foundation
 CIRCULATING IRISIN AND PHYSICAL ACTIVITY

were determined. In all statistical tests, a P-value of < 0
05 was and SAD were not significantly different between the two
considered significant. groups.
As expected, the FIT index, a measure of each participant’s
Results habitual physical activity, was low (14
2  9
1 and
12
5  9
6) and not significantly different between groups.
All of the 164 adults (81 healthy controls and 83 with DMT2)
The FIT index was positively correlated with circulating irisin
were included in the analysis. The clinical and laboratory
(R = 0
20, P = 0
03) in the control group but not in DMT2
characteristics of the subjects are presented in Table 1. Signifi-
subjects (R = 0
04, P = 0
74) (Table 2 and Fig. 2). The corre-
cantly higher levels of circulating irisin were observed in DMT2
lation between FIT index and irisin remained borderline sig-
subjects compared to healthy controls (P < 0
001) (Fig. 1).
nificant after adjusting for LBM (R = 0
23; P = 0
05). BMI
Additionally, systemic glucose, total cholesterol and triglyce-
(R = 0
22, P = 0
04) and waist circumference (r = 0
23,
rides as well as systolic blood pressure were significantly
P = 0
04) were also positively correlated with circulating iri-
higher in subjects with DMT2 than in control subjects (Table 1).
sin levels in the healthy control group. In the DMT2 group,
Other parameters including age, gender, BMI, waist, hips, LBM
LBM (R = 0
26, P = 0
02) and diastolic blood pressure
(R = 0
25, P = 0
02) were negatively correlated with circu-
lating irisin levels (Table 2).
Table 1 Anthropometric and clinical characteristics of subjects Intertertile range for FIT index was assessed to examine the
Control DMT2 associations between the levels of physical activity (low,
(n = 81) (n = 83) P value moderate and high) and circulating irisin. It was observed
that circulating irisin levels were significantly higher in tertile
Gender, (M/F) 42/39 35/48 0
21
3 (highest physical activity) compared to tertile 1 (lowest
Age, (years) 51
6  10
9 54
3  10
3 0
10 physical activity) in healthy controls (0
75  0
07 vs.
BMI, (kg/m )2
29
6  4
3 29
4  4
7 0
76 0
49  0
06). In contrast, the differences were not significant
in DMT2 subjects although there was a similar trend
Lean body mass, 48
3  6
9 47
4  7
0 0
40
(kg) (Fig. 2).

FIT index 14
2  9
1 12
5  9
6 0
09

Discussion
Waist circumference, 97
2  12
2 96
1  17
7 0
65
(cm)
In this study, we observed a significantly higher circulating
irisin in DMT2 subjects compared to healthy controls. We also
Hip circumference, 104
6  13
1 103
2  15
6 0
53 observed that the FIT index was positively associated with
(cm)
Sagittal abdominal 24
4  9
0 24
5  5
0 0
91
diameter, (cm)
Systolic blood 121
4  12
4 125
6  12
8 0
04
pressure, (mmHg)
Diastolic blood 79
9  10
0 78
7  7
0 0
35
pressure, (mmHg)
Glucose, (mmol/L) 4
8  1
1 12
7  3
6 < 0
001
Triglycerides, 1
6  0
73 2
4  1
4 < 0
001
(mmol/L)
Total cholesterol, 5
2  1
1 5
6  1
1 0
02
(mmol/L)
HDL cholesterol, 0
94  0
25 0
88  0
33 0
16
(mmol/L)
LDL cholesterol, 3
5  1
1 3
6  0
87 0
41
(mmol/L)
Irisin, (lg/mL) 0
59  0
03 0
89  0
03 0
001* Figure 1 Mean irisin levels in healthy controls and DMT2
subjects.
*Adjusted for lean body mass and FIT index.

European Journal of Clinical Investigation Vol 45 777

 N. M. AL-DAGHRI ET AL. www.ejci-online.com

Table 2 Correlations of irisin with metabolic parameters and FIT index

Overall Control DMT2
R P value R P value R P value

n 164 81 83
Age, (years) 0
004 0
95 0
09 0
39 0
09 0
41
2
BMI, (kg/m ) 0
12 0
11 0
22 0
04* 0
04 0
75
Lean body mass, (kg) 0
12 0
12 0
02 0
89 0
26 0
02*
Waist circumference, (cm) 0
12 0
13 0
23 0
04* 0
05 0
65
Hip circumference, (cm) 0
13 0
08 0
19 0
07 0
08 0
44
Sagittal abdominal diameter, (cm) 0
03 0
72 0
06 0
62 0
02 0
84
Systolic blood pressure, (mmHg) 0
03 0
67 0
06 0
61 0
12 0
28
Diastolic blood pressure, (mmHg) 0
15 0
04* 0
09 0
42 0
25 0
02*
Glucose, (mmol/L) 0
02 0
80 0
04 0
69 0
06 0
57
Triglycerides, (mmol/L) 0
03 0
69 0
04 0
71 0
03 0
77
Total cholesterol, (mmol/L) 0
06 0
46 0
15 0
18 0
04 0
75
HDL cholesterol, (mmol/L) 0
04 0
61 0
02 0
87 0
08 0
44
LDL cholesterol, (mmol/L) 0
03 0
66 0
14 0
19 0
10 0
37
FIT index 0
12 0
14 0
20 0
03* 0
04 0
74
Data presented as coefficient (R). *Significant at P < 0
05.

1·2 Tertile 1 Tertile 2 Tertile 3

1·0

1 0·86
0·85 * 0·81
0·75
0·8 0·67 0·69
Irisin (ug/ml)

0·54
0·6 0·49

0·4

0·2

0
Over all Control Diabetic Figure 2 Serum irisin levels based on
tertiles of FIT index.
* indicates mean serum irisin of tertile 3 is significanlty greater than tertile 1 (P < 0·05)

circulating irisin in controls, whilst no such association was
observed in DMT2 subjects. Additionally, by splitting the sub-
jects into tertiles based on their FIT index, we observed signif-
icantly higher levels of irisin in tertile 3 compared to tertile 1 in
controls but not in DMT2 subjects.
Higher circulating levels of irisin in DMT2 subjects may
indicate the dysregulation of irisin. Although a few studies
have reported low levels of irisin in metabolic disease states
[20–22,24], other studies have shown an increased level of irisin
in DMT2 and other metabolic conditions [18,23,37]. Previous
reports suggested that higher irisin levels in DMT2 and other
metabolic diseases may be a compensatory mechanism
[10,25,37]. In a combined in vivo and in vitro study, Kurdiova
et al. [18] highlighted that FNDC5/irisin was discordantly

778 ª 2015 Stichting European Society for Clinical Investigation Journal Foundation

regulated in the diabetic muscle and myotubes in vitro,
suggesting that whole-body factors (e.g. glucose and fatty
acids) may also be important for irisin regulation [18]. Recently,
Park et al. [23] reported significantly higher irisin levels in
subjects with metabolic syndrome (MetS) compared to those
without. They postulated that impaired irisin signalling in MetS
may have led to the unregulated release of irisin. These obser-
vations strengthen our present findings and assumption of iri-
sin deregulation in subjects with DMT2. In studies where
circulating irisin levels were found to be lower in DMT2 than in
non-DMT2 subjects [21,22], the lower levels were attributed to
the impairment of muscle PGC-1a expression and functions in
DMT2. Discrepancies in the levels of irisin in DMT2 may also
have a link to glycated haemoglobin (HbA1c) [21].
We observed a positive correlation between FIT score and
serum irisin in controls. However, no such association of irisin
level with physical activity was noted in DMT2 subjects. The
possible reason for this difference may again relate to the
metabolic dysfunction in DMT2 [23]. It has been observed that
altered metabolic states could lead to abnormalities in the
exercise-dependent pathway in the expression of PGC-1a
[38–41]. Such abnormalities would also affect the PGC-1a-
dependent fibronectin type III domain-containing 5 (FNDC5)
expression. Other reasons like insulin resistance in DM condi-
tion could also affect the irisin regulation. Although our results
in control subjects are supported by studies on acute exercise
training [11,12] and in obese children where irisin level
increased post-intervention [14], findings in adults failed to
observe a similar rise in irisin levels with long-term exercise
training [12,15,16]. A recent time course study by Huh et al. [42]
found an immediate increase in circulating levels of irisin after
a high-intensity exercise which declined after 1 h. Therefore, a
time period for irisin measurements is also an important factor,
as muscle mass gain induced by exercise could explain the rise
in irisin levels.
There were certain limitations in this study. Firstly, it was
possible that our observations in DMT2 condition were not
controlled for important glycemic variables such as HbA1c,
insulin, HOMA-IR, variations in disease duration, diabetes
complications and medications that were not included in the
questionnaire. Secondly, the cross-sectional design of the study
limits the irisin measurement over different time points and/or
in relation to acute exercise training.
In conclusion, our findings suggest that in non-DMT2 con-
trols, the levels of circulating irisin are positively associated
with physical activity. An increasing trend in irisin was
observed after splitting the controls into tertiles based on their
FIT index. However, this relationship seems to be lost in DMT2
subjects, probably because of the wider distribution of irisin in
this group. Thus, data from the present study support the
influence of habitual physical activity on circulating irisin levels
CIRCULATING IRISIN AND PHYSICAL ACTIVITY
in non-DMT2 controls, and the dysregulation of irisin in DMT2.
Further research is needed to study the influence of habitual
physical activity on circulating irisin levels in different meta-
bolic states including insulin resistance markers to understand
its mechanisms, signalling pathways and the possible reason
associated with discordant regulation in metabolic disease
states.
Acknowledgements
The project was financially supported by King Saud University,
Vice Deanship of Scientific Research chairs.
Declaration of interest
The authors declare no conflict of interest.
Author contribution
NMA, MSA, OSA and SR conceptualized the study. OEA and
SR performed the experiment and researched the data. SR,
MKP and HA wrote the manuscript. GT, PGM, SS and GPC
reviewed/edited the manuscript. All authors read and
approved the final version of the manuscript.
Address
Biomarkers Research Program, Biochemistry Department,
College of Science, King Saud University, Riyadh 11451,
Saudi Arabia (N. M. Al-Daghri, M. S. Alokail, S. Rahman, O.
S. Amer, O. S. Al-Attas, S. Sabico); Prince Mutaib Chair for
Biomarkers of Osteoporosis, Biochemistry Department, Col-
lege of Science, King Saud University, Riyadh 11451, Saudi
Arabia (N. M. Al-Daghri, M. S. Alokail, O. S. Al-Attas, H.
Alfawaz); Department of Food Science and Nutrition, College
of Food Science and Agriculture, King Saud University,
Riyadh 11451, Saudi Arabia (H. Alfawaz); Division of
Translational and Systems Medicine, Warwick Medical
School, University of Warwick, Coventry, UK (G. Tripathi, P.
G. McTernan, M. K. Piya); First Department of Pediatrics,
Athens University Medical School, Athens 11527, Greece
(G. P. Chrousos).
Correspondence to: Nasser M. Al-Daghri, Biomarkers Research
Program, Biochemistry Department, College of Science, King
Saud University, 11451, Riyadh, Saudi Arabia. Tel.:
0096614675939; fax: 0096614675931; e-mail:
aldaghri2011@gmail.com
Received 10 February 2015; accepted 19 May 2015
References
1 Bostrom P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC et al. A
PGC1-a-dependent myokine that drives brown-fat-like development
of white fat and thermogenesis. Nature 2012;481:463–8.
European Journal of Clinical Investigation Vol 45 779
 N. M. AL-DAGHRI ET AL.
2 Lecker SH, Zavin A, Cao P, Arena R, Allsup K, Daniels KM et al.
Expression of the irisin precursor FNDC5 in skeletal muscle
correlates with aerobic exercise performance in patients with heart
failure. Circ Heart Fail 2012;5:812–8.
3 Wu J, Bostrom P, Sparks LM, Ye L, Choi JH, Giang A-H et al. Beige
adipocytes are a distinct type of thermogenic fat cell in mouse and
human. Cell 2012;150:366–76.
4 Swick AG, Orena S, O’Connor A. Irisin levels correlate with energy
expenditure in a subgroup of humans with energy expenditure
greater than predicted by fat free mass. Metabolism 2013;62:1070–3.
5 Kokkinos P, Myers J. Exercise and physical activity clinical outcomes
and applications. Circulation 2010;122:1637–48.
6 Haskell WL, Lee I, Pate RR, Powell KE, Blair SN, Franklin BA et al.
Physical activity and public health: updated recommendation for
adults from the American College of Sports Medicine and the
American Heart Association. Med Sci Sports Exerc 2007;39:1423.
7 Colberg SR, Sigal RJ, Fernhall B, Regensteiner JG, Blissmer BJ, Rubin
RR et al. Exercise and Type 2 Diabetes The American College of
Sports Medicine and the American Diabetes Association: joint
position statement. Diabetes Care 2010;33:e147–67.
8 Egan B, Zierath JR. Exercise metabolism and the molecular
regulation of skeletal muscle adaptation. Cell Metab 2013;17:
162–84.
9 Wen CP, Wai JPM, Tsai MK, Yang YC, Cheng TYD, Lee M-C et al.
Minimum amount of physical activity for reduced mortality and
extended life expectancy: a prospective cohort study. The Lancet
2011;378:1244–53.
10 Huh JY, Panagiotou G, Mougios V, Brinkoetter M, Vamvini MT,
Schneider BE et al. FNDC5 and irisin in humans: I. Predictors of
circulating concentrations in serum and plasma and II. mRNA
expression and circulating concentrations in response to weight loss
and exercise. Metabolism 2012;61:1725–38.
11 Kraemer RR, Shockett P, Webb ND, Shah U, Castracane VD. A
transient elevated irisin blood concentration in response to
prolonged, moderate aerobic exercise in young men and women.
Horm Metab Res 2014;46:150–4.
12 Huh JY, Mougios V, Skraparlis A, Kabasakalis A, Mantzoros CS.
Irisin in response to acute and chronic whole-body vibration
exercise in humans. Metabolism 2014;63:918–21.
13 Polyzos SA, Kountouras J, Shields K, Mantzoros CS. Irisin:
a renaissance in metabolism. Metabolism 2013;62:1037–44.
14 Bluher S, Panagiotou G, Petroff D, Markert J, Wagner A, Klemm T
et al. Effects of a 1-year exercise and lifestyle intervention on irisin,
adipokines, and inflammatory markers in obese children. Obesity
2014;22:1701–8.
15 Pekkala S, Wiklund PK, Hulmi JJ, Ahtiainen JP, Horttanainen M,
Pollanen E et al. Are skeletal muscle FNDC5 gene expression and
irisin release regulated by exercise and related to health? J Physiol
2013;591:5393–400.
16 Hecksteden A, Wegmann M, Steffen A, Kraushaar J, Morsch A,
Ruppenthal S et al. Irisin and exercise training in humans-Results
from a randomized controlled training trial. BMC Med 2013;
11:235.
17 Norheim F, Langleite TM, Hjorth M, Holen T, Kielland A, Stadheim
HK et al. The effects of acute and chronic exercise on PGC-1a, irisin
and browning of subcutaneous adipose tissue in humans. FEBS J
2014;281:739–49.
18 Kurdiova T, Balaz M, Vician M, Maderova D, Vlcek M, Valkovic L
et al. Are skeletal muscle & adipose tissue Fndc5 gene expression
and irisin release affected by obesity, diabetes and exercise? In vivo
& in vitro studies. J Physiol 2014;592:1091–107.
780 ª 2015 Stichting European Society for Clinical Investigation Journal Foundation
www.ejci-online.com
19 Timmons JA, Baar K, Davidsen PK, Atherton PJ. Is irisin a human
exercise gene? Nature 2012;488:E9–10.
20 Choi Y-K, Kim M-K, Bae KH, Seo H, Jeong J-Y, Lee W-K et al. Serum
irisin levels in new-onset type 2 diabetes. Diabetes Res Clin Pract
2013;100:96–101.
21 Liu J-J, Wong MD, Toy WC, Tan CS, Liu S, Ng XW et al. Lower
circulating irisin is associated with type 2 diabetes mellitus.
J Diabetes Complications 2013;27:365–9.
22 Moreno-Navarrete JM, Ortega F, Serrano M, Guerra E, Pardo G,
Tinahones F et al. Irisin is expressed and produced by human
muscle and adipose tissue in association with obesity and insulin
resistance. J Clin Endocrinol Metab 2013;98:E769–78.
23 Park KH, Zaichenko L, Brinkoetter M, Thakkar B, Sahin-Efe A,
Joung KE et al. Circulating Irisin in relation to insulin resistance and
the metabolic syndrome. J Clin Endocrinol Metab 2013;98:4899–907.
24 Stengel A, Hofmann T, Goebel-Stengel M, Elbelt U, Kobelt P, Klapp
BF. Circulating levels of irisin in patients with anorexia nervosa and
different stages of obesity–Correlation with body mass index.
Peptides 2013;39:125–30.
25 Piya MK, Harte AL, Sivakumar K, Tripathi G, Voyias PD, James S
et al. The identification of irisin in human cerebrospinal fluid:
influence of adiposity, metabolic markers and gestational diabetes.
Am J Physiol Endocrinol Metab 2014;306:E512–8.
26 Bostr€ om PA, Fernandez-Real JM, Mantzoros C. Irisin in humans:
recent advances and questions for future research. Metab: Clin Exp
2014;63:178.
27 Al-Daghri NM, Al-Attas OS, Alokail MS, Alkharfy KM, Yousef M,
Sabico SL et al. Diabetes mellitus type 2 and other chronic non-
communicable diseases in the central region, Saudi Arabia (Riyadh
cohort 2): a decade of an epidemic. BMC Med 2011;9:76.
28 Al-Nozha MM, Al-Hazzaa HM, Arafah MR, Al-Khadra A,
AlMazrou YY, Al-Maatouq MA et al. Prevalence of physical activity
and inactivity among Saudis aged 30–70 years: a population-based
cross-sectional study. Saudi Med J 2007;28:559–68.
29 Al-Daghri NM, Alkharfy KM, Al-Saleh Y, Al-Attas OS, Alokail MS,
Al-Othman A et al. Modest reversal of metabolic syndrome
manifestations with vitamin D status correction: a 12-month
prospective study. Metabolism 2012;61:661–6.
30 Kasari DS. The effects of exercise on serum lipid levels in college
women. Unpublished master’s thesis. University of Montana; 1976.
31 Lease HJ, Bond MJ. Correspondence between alternate measures of
maladaptive exercise, and their associations with disordered eating
symptomatology. J Behav Addict 2013;2:153–9.
32 McKune AJ, Semple SJ, Smith LL, Wadee AA. Complement,
immunoglobulin and creatine kinase response in black and white
males after muscle-damaging exercise. S Afr J Sports Med 2009;21:47–52.
33 Sharkey BJ, Gaskill SE. Fitness and Health, 6th edn: Champaign, IL:
Human Kinetics; 2007.
34 Hume R. Prediction of lean body mass from height and weight.
J Clin Pathol 1966;19:389–91.
35 Al-Daghri NM, Al-Attas OS, Alokail MS, Alkharfy KM, Yousef M,
Vinodson B et al. Maternal inheritance of circulating irisin in
humans. Clin Sci 2014;126:837–44.
36 Al-Daghri NM, Alkharfy KM, Rahman S, Amer OE, Vinodson B,
Sabico S et al. Irisin as a predictor of glucose metabolism in children:
sexually dimorphic effects. Eur J Clin Invest 2014;44:119–24.
37 Bostrom PA, Fernandez-Real JM. Metabolism: irisin, the metabolic
syndrome and follistatin in humans. Nat Rev Endocrinol
2014;10:11–2.
38 Patti ME, Butte AJ, Crunkhorn S, Cusi K, Berria R, Kashyap S et al.
Coordinated reduction of genes of oxidative metabolism in humans

with insulin resistance and diabetes: potential role of PGC1 and
NRF1. Proc Natl Acad Sci 2003;100:8466–71.
39 Skov V, Glintborg D, Knudsen S, Jensen T, Kruse TA, Tan Q et al.
Reduced expression of nuclear-encoded genes involved in
mitochondrial oxidative metabolism in skeletal muscle of insulin-
resistant women with polycystic ovary syndrome. Diabetes
2007;56:2349–55.
40 Højlund K, Bostr€ om P. Irisin in obesity and type 2 diabetes.
J Diabetes Complications 2013;27:303–4.
CIRCULATING IRISIN AND PHYSICAL ACTIVITY
41 Hernandez-Alvarez MI, Thabit H, Burns N, Shah S, Brema I, Hatunic
M et al. Subjects with early-onset type 2 diabetes show defective
activation of the skeletal muscle PGC-1a/mitofusin-2 regulatory
pathway in response to physical activity. Diabetes Care 2010;33:645–51.
42 Huh JY, Mougios V, Kabasakalis A, Fatouros I, Siopi A, Douroudos
II et al. Exercise-induced irisin secretion is independent of age or
fitness level and increased irisin may directly modulate muscle
metabolism through AMPK activation. J Clin Endocrinol Metab
2014;99:2154–61.
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