Higher baseline irisin concentrations are associated with greater reductions in glycemia and insulinemia after weight loss in obese subjects

Abstract

Irisin is assumed to be a relevant link between muscle and weight maintenance as well as to mediate exercise benefits on health. The aim of this study was to assess the possible associations between irisin levels and glucose homeostasis in obese subjects with metabolic syndrome (MetS) following an energy-restricted treatment. Ninety-six adults with excessive body weight and MetS features underwent a hypocaloric dietary pattern for 8 weeks, within the RESMENA randomized controlled trial (www.clinicaltrials.gov; NCT01087086). After the intervention, dietary restriction significantly reduced body weight and evidenced a dietary-induced decrease in circulating levels of irisin in parallel with improvements on glucose homeostasis markers. Interestingly, participants with higher irisin values at baseline (above the median) showed a greater reduction on glucose (P=0.022) and insulin (P=0.021) concentrations as well as on the homeostasis model assessment index (P=0.008) and triglycerides (P=0.006) after the dietary intervention, compared with those presenting low-irisin baseline values (below the median). Interestingly, a positive correlation between irisin and carbohydrate intake was found at the end of the experimental period. In conclusion, irisin appears to be involved in glucose metabolism regulation after a dietary-induced weight loss.

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OPEN
SHORT COMMUNICATION
Higher baseline irisin concentrations are associated with greater
reductions in glycemia and insulinemia after weight loss
in obese subjects
P Lopez-Legarrea
1,2
, R de la Iglesia
1
, AB Crujeiras
3,4,5
, M Pardo
3,4
, FF Casanueva
4
, MA Zulet
1,3
and JA Martinez
1,3
Irisin is assumed to be a relevant link between muscle and weight maintenance as well as to mediate exercise benefits on health.
The aim of this study was to assess the possible associations between irisin levels and glucose homeostasis in obese subjects
with metabolic syndrome (MetS) following an energy-restricted treatment. Ninety-six adults with excessive body weight
and MetS features underwent a hypocaloric dietary pattern for 8 weeks, within the RESMENA randomized controlled trial
(www.clinicaltrials.gov; NCT01087086). After the intervention, dietary restriction significantly reduced body weight and evidenced a
dietary-induced decrease in circulating levels of irisin in parallel with improvements on glucose homeostasis markers. Interestingly,
participants with higher irisin values at baseline (above the median) showed a greater reduction on glucose (P¼0.022) and insulin
(P¼0.021) concentrations as well as on the homeostasis model assessment index (P¼0.008) and triglycerides (P¼0.006) after
the dietary intervention, compared with those presenting low-irisin baseline values (below the median). Interestingly, a positive
correlation between irisin and carbohydrate intake was found at the end of the experimental period. In conclusion, irisin appears to
be involved in glucose metabolism regulation after a dietary-induced weight loss.
Nutrition & Diabetes (2014) 4, e110; doi:10.1038/nutd.2014.7; published online 24 February 2014
INTRODUCTION
Obesity is a worldwide health burden, accompanied by a number
of comorbidities including glucose intolerance, insulin resistance
and type 2 diabetes.
1
In this context, the myokine irisin,
2
which is a
cleavage product of the type I membrane protein fibronectin type
III domain-containing 5, has been hypothesized as a target to
counteract obesity and type 2 diabetes.
3,4
Irisin is expressed in the
muscle and the adipose tissue and has been associated with
adiposity and body weight in animals
5,6
and humans.
7,8
However,
the precise role and underlying mechanisms concerning irisin
actions and signaling pathways remain incompletely understood.
The aim of this research was to assess changes on circulating
irisin concentrations in obese subjects presenting metabolic
syndrome (MetS) features after a treatment designed to lose
weight and to analyze the potential relationships of this myokine
with glucose homeostasis after dieting.
MATERIALS AND METHODS
Study protocol
This research reports the findings of the 8-week intervention period of
the RESMENA randomized intervention trial (www.clinicaltrials.gov;
NCT01087086), which was conducted following the CONSORT 2010
criteria. A full list of inclusion criteria, as well as a complete description
of the study methodology can be found in earlier publications.
9,10
Briefly,
participants were randomized into two intervention groups, with the same
energy restriction (–30% E), but differing mainly in the carbohydrate/
protein ratio and meal frequency: control group supplying 55% E from
CHO and 15% E from proteins within a 3–5 meals per day pattern,
and RESMENA group providing 40% E from CHO and 30% E from proteins
within a 7 meals per day plan.
Subjects
Ninety-six adults (mean age ¼50 years old; range 21–70 years old)
with excessive body weight (mean body mass index ¼35.9 kg m
–2
; range
26.9–49.4 kg m
–2
) suffering MetS according to the International Diabetes
Federation criteria completed the intervention period. All the participants
gave a written informed consent to participate as approved by the Ethics
Committee of the University of Navarra (065/2009) and in accordance with
the Declaration of Helsinki.
Participant’s dietary intake was assessed by means of 48-h weighed
records at baseline and at the end of the intervention and further analyzed
using the DIAL software (Alce Ingenieria, Madrid, Spain). Subjects were
asked to maintain their usual activity levels during the study, which was
monitored at the beginning and endpoint with a validated 24-h physical
activity questionnaire.
9
Anthropometric measurements and body composition determinations
were performed, as described elsewhere.
9
Overnight fasting plasma levels
of glucose and triglycerides were measured in an autoanalyzer Pentra
C-200 (HORIBA ABX, Madrid, Spain) with specific kits from this company.
Insulin concentrations were determined with an enzyme-linked
immunosorbent assay kit (Mercodia, Uppsala, Sweden) in a Triturus
autoanalyzer (Grifols SA, Barcelona, Spain) and the homeostasis model
(homeostatic model assessment-insulin resistance (HOMA-IR)) was applied
to estimate insulin resistance.
Irisin plasma levels were determined using a commercial enzyme-linked
immunosorbent assay kit following the manufacturer’s instructions (Irisin
ELISA kit EK-067–52; Phoenix Pharmaceuticals, Inc., Burlingame, CA, USA),
1
Department of Nutrition, Food Science and Physiology, University of Navarra, Pamplona, Spain;
2
Faculty of Health Science, Universidad Autonoma de Chile, Santiago, Chile;
3
CIBERObn, Carlos III Health Institute, Madrid, Spain;
4
Laboratory of Molecular and Cellular Endocrinology, Health Research Institute (IDIS), University of Santiago Hospital Complex
(CHUS) and Santiago de Compostela University (USC), Santiago de Compostela, Spain and
5
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute
(IDIBELL), Barcelona, Spain. Correspondence: Professor JA Martinez, Department of Nutrition, Food Science and Physiology, University of Navarra, C/Irunlarrea 1, Pamplona 31008,
Spain.
E-mail: jalfmtz@unav.es
Received 5 September 2013; revised 4 January 2014; accepted 18 January 2014
Citation: Nutrition & Diabetes (2014) 4, e110; doi:10.1038/nutd.2014.7
&
2014 Macmillan Publishers Limited All rights reserved 2044-4052/14
www.nature.com/nutd

on a spectrophotometric reader at a wavelength of 450 nm (Versamax
Microplate Reader, East Falmouth, MA, USA). This test provided a range of
detection of 0.066–1024ng ml
–1
and exhibited a coefficient of variation of
6–10% inter- and intra-assay. The samples were kept at 80 1C and were
analyzed immediately after the experiment was ended.
Statistical analysis
The sample size of this secondary analysis was calculated for an a¼0.05
and a power of 80% based on the waist circumference reduction, as
described elsewhere.
9
Normality distributions of the measured variables
were determined according to the Shapiro–Wilk test. Irisin plasma levels
were not normally distributed, but based on the sample size (n460) a
parametric test was performed. Indeed, after analysis with a log
transformation of irisin values the statistical outcomes were maintained.
Differences between baseline and endpoint values within groups were
analyzed by a paired t-test. Analyses between dietary groups were
performed with unpaired t-tests. A multiple linear regression analysis was
applied in order to assess the potential relationships among irisin with
anthropometric and biochemical measurements (95% confidence interval).
The median value of irisin baseline concentrations was considered as the
cutoff for analyzing the effect of high- or low-irisin levels on glucose
regulatory factors, as previously applied.
11
This tool is based on the
assignment of the studied population into two groups of disease risk. The
association between irisin levels and carbohydrate intake was assessed
using the parametric Pearson correlation. Specific statistical analyses
(analysis of covariance) were performed after excluding outlier values in
order to control the regression to the mean phenomenon. Statistical
analysis was performed using SPSS15.1 software (SPSS Inc., Chicago, IL,
USA). An alpha level of 0.05 was set up for determining statistically
significant differences. Data are reported as mean±s.e.
RESULTS
At the beginning of the intervention, there were no differences
between groups in any of the anthropometric and routine
biochemical markers (P40.05). After the intervention, an improve-
ment (reduction) was observed on these measurements with
apparently equal effectiveness between the two dietary treat-
ments (P40.05, Table 1), except for adiponectin, which was
increased in both groups, but without reaching statistical
significance. Changes in irisin concentrations were similar
(P40.05) in the control group ( 87.3±18.4 ng ml
–1
) as compared
with the RESMENA group ( 59.8±11.8 ng ml
–1
), after following
the energy-restricted treatment. Therefore, both groups were
merged for subsequent analyses. Considering the whole sample,
participant’s mean body weight loss was 6.9±3.0 kg and irisin
plasma concentrations diminished (Figure 1a) in association with
changes in body weight (r¼0.21; P¼0.046) and fat mass (r¼0.22;
P¼0.037). As the main objective of this study was to evaluate the
potential role of irisin on glucose homeostasis and given that
some of the participants were diabetic, a preliminary analysis
separating non-diabetic and diabetic participants was also
performed. Differences were found for glucose concentrations
and HOMA index between both groups after the nutritional
intervention with energy restriction, but similar outcomes were
found concerning irisin concentrations (data not shown).
Similar values were found concerning physical activity assess-
ments at the beginning and at the end of the intervention in both
dietary groups. Moreover, the regression analysis showed no
relationships between physical activity factor and irisin levels
changes (P¼0.736). An association of circulating glucose
(B¼0.134, 95% confidence interval: 0.245 to 0.024;
P¼0.018) and irisin concentrations changes was found, irrespec-
tive of confounding factors: gender, age, diet, body weight loss
and irisin baseline values.
Interestingly, after adjusting for gender, age and weight loss,
participants belonging to the high-irisin group at baseline
(4308.0 ng ml
–1
) evidenced significantly greater reductions
(Figure 1b) on glucose (P¼0.022), insulin (P¼0.021), HOMA index
(P¼0.008) and triglycerides (P¼0.006), compared with those
belonging to the low-irisin group at baseline (o308.0 ng ml
–1
).
Furthermore, the decrease in irisin concentrations was signifi-
cantly greater (Po0.001) within the group with high-irisin values
at baseline ( 126.6±15.9 ng ml
–1
) than within the lower
irisenemia group ( 18.2±9.1 ng ml
–1
). After 8 weeks of nutri-
tional intervention, irisin concentrations were positively correlated
with carbohydrate intake (cereals, pulse, fruits and vegetables;
r¼0.234, P¼0.023; Figure 1c).
DISCUSSION
This study evidenced that irisin per se may exert an effect on the
reduction of glucose, insulin and triglycerides concentrations after
prescribing an 8-week nutritional intervention to obese subjects
with MetS traits.
Irisin is a recently discovered muscle-derived hormone, whose
secretion is induced by exercise.
2
This myokine has been shown to
be able to increase energy expenditure, and therefore, it has been
proposed to have a potential role in obesity and diabetes
treatments.
2,12–14
Since discovery, a number of original studies
have addressed various aspects of the biology of irisin.
15
However,
the regulation and specific role of irisin in human’s glucose
metabolism remain still unclear. Thus, the main objective of the
current research was to investigate the potential relationships
between irisin concentrations and glucose homeostasis, after
dieting.
Table 1. Changes in selected anthropometric and biochemical parameters within each dietary group (control and RESMENA) after the 8-week
intervention and comparison between groups
Control group RESMENA group Difference between diet
groups (P-value)
Baseline Endpoint P-value Baseline Endpoint P-value
Body weight (kg) 99.5±2.8 92.7±2.7 o0.001 100.0±2.4 92.9±2.3 o0.001 0.555
BMI (kg m
–2
) 36.2±0.7 33.7±0.7 o0.001 35.6±0.6 33.0±0.6 o0.001 0.732
Fat mass (%) 39.1±1.1 36.2±1.1 o0.001 39.2±0.9 36.4±1.0 o0.001 0.854
Fat mass (kg) 39.0±1.6 33.7±1.5 o0.001 39.2±1.4 33.8±1.3 o0.001 0.886
Glucose (mg dl
–1
) 121.0±5.0 108.0±2.0 0.006 123.8±5.5 110.2±3.8 0.016 0.939
Insulin (mUml
–1
) 15.3±1.7 9.3±1.1 o0.001 14.4±1.2 9.1±0.9 o0.001 0.557
HOMA 4.7±0.6 2.6±0.3 o0.001 4.5±0.4 2.6±0.3 o0.001 0.686
Triglycerides (mg dl
–1
) 176±13 145±10 0.005 194±18 151±14 o0.001 0.421
Irisin (ng ml
–1
) 412.3±31.6 326.7±22.6 o0.001 299.4±16.3 239.6±8.8 o0.001 0.234
Leptin (ng ml
–1
) 22.4±2.3 14.8±1.8 o0.001 20.2±2.1 12.8±1.6 o0.001 0.883
Adiponectin (ng ml
–1
) 13.6±1.5 13.8±1.3 0.863 12.1±1.3 17.6±3.3 0.127 0.152
Abbreviations: BMI, body mass index; HOMA, homeostasis model assessment.
Irisin and glucose homeostasis
P Lopez-Legarrea et al
2
Nutrition & Diabetes (2014), 1 – 4 &2014 Macmillan Publishers Limited

The study was designed as a randomized controlled nutritional
intervention comparing two energy-restricted dietary treatments.
9
Both control and RESMENA dietary strategies proved to be
effective for improving MetS disturbances by lowering
anthropometric and biochemical markers, being these outcomes
in agreement with other studies concerning hypocaloric diets.
16
However, no differences between treatments were observed for
any of the studied variables including irisin. For that reason, the
sample was merged and considered as a whole for the
subsequent analyses regarding irisin concentrations and its
potential associations with glucose metabolism.
First, changes on irisin concentrations after the 8 weeks of
nutritional intervention were evaluated. This study evidenced that
irisin plasma concentrations decreased after the energy restriction
program and the subsequent weight loss, independently of the
dietary group. This finding is in agreement with a previous study
that reported a reduction in irisin levels after surgically induced
weight markdown.
8
Then, the potential role of irisin on glucose homeostasis-related
parameters was analyzed in order to reach the main objective of
the research. The prime finding of the current investigation was
that higher irisin concentrations at the beginning of the
intervention were associated with greater reductions on glucose
and insulin concentrations as well as on the HOMA index,
independently of body weight loss. Although this outcome should
be carefully examined, similar results have been reported in
children by Al-Daghri et al.
17
where a crucial role for irisin in
glucose homeostasis was suggested. On the other hand, those
individuals with higher irisin concentrations at the beginning of
the intervention also achieved higher beneficial effects regarding
the lowering of triglycerides concentrations. This effect could be
explained by the fact that triglycerides levels have been revealed
to positively correlate with glucose levels.
18
Thus, the effects of
irisin on the changes of glucose concentrations may have been
subsequently reflected on triglycerides. In addition, taking into
account that irisin has been evidenced to increase energy
expenditure,
19
the greater reduction observed in triglycerides
according to the high-irisin levels at baseline may be also due to a
higher utilization of triglycerides as energy substrate. Previous
studies have also evidenced an inverse association of irisin levels
with triglycerides concentrations.
20
Taking together these
outcomes, it can be suggested that irisin may be involved in the
regulation of glucose homeostasis in obese subjects presenting
MetS features. Thus, irisin could mean a physiological feedback to
counteract potential glucose metabolism-related disturbances
associated to an excessive body weight state. Irisin would seem
to be increased in unfavorable metabolic situations acting as a
compensatory triggering mechanism. Other authors have likewise
claimed that the increase in irisin under obesity conditions may
indicate a physiological adaptation to improve glucose tolerance,
which is often impaired in obese subjects.
3
Indeed, this behavior
has been observed predominantly in individuals with metabolic
disease
21
as it is the condition of our study population. However,
other studies reported associations between plasma irisin levels
and important metabolic factors in non-diabetic subjects, but not
in individuals with type 2 diabetes.
4,22
Our suggested corollary
would be that irisin is increased in metabolically altered situations
and may diminish as a consequence of the weight loss, as irisin is
then ‘less’ needed to restore the altered metabolic state. Thus, the
theory about a possible irisin resistance appears similar to the
well-known leptin insensitivity in obesity and cannot be
discarded
21
as has been reported for leptinemia and insulinemia
after dieting.
11
The association between irisin concentrations and carbohydrate
intake was related to the consumption of some sources of
carbohydrates (cereals, pulse, fruits and vegetables). This outcome
may be explained because the dietary modifications during the
hypocaloric intervention evolved with shifts in carbohydrate
consumption within the energy restriction. Thus, irisin could be
increased in response to the dietary pattern, depending on the
carbohydrate content, in order to prevent/improve the rise on
glucose, insulin or HOMA index values, linked to latter damage on
multiple organs.
23
This finding is interesting given that modifying
the macronutrient distribution is a recurrent approach for treating
obese and MetS patients.
24
The observed results appear to be irrespective to the physical
activity, as patients in this study maintained the same physical
activity level along the intervention. The statistical adjustments for
sex did not revealed specific differences between males and
females concerning the analyzed irisin outcomes. A limitation of
this study is that it demonstrated an association but not evidenced
causation. Moreover, the methods to assess the dietary intake and
physical activity were based on questionnaires, which could bias the
results interpretation. Also, some other relevant measurements in
relation to glucose metabolism, such as OGTT or Clamp-test would
be appropriate. However, the design of the current trial based on a
Figure 1. Irisin changes from baseline (week 0) to the end (week 8)
of the intervention (a); changes in glucose, insulin, HOMA index and
triglycerides, depending on irisin baseline levels after the interven-
tion of 8 weeks duration (b); and irisin correlation with carbohydrate
intake (cereals, pulse, fruits and vegetables) at the endpoint of the
intervention (c).
Irisin and glucose homeostasis
P Lopez-Legarrea et al
3
&2014 Macmillan Publishers Limited Nutrition & Diabetes (2014), 1 – 4

nutritional intervention involving a quite large human sample is
indeed a valuable feature enabling pre- and post-test comparisons
within subjects. An effect of regression to the mean could not be
attributed since pertinent statistical procedures were performed in
order to control this phenomenon.
This research concerns the investigation of a potential role of
irisin on impaired glucose homeostasis associated to obesity and,
consequently, the metabolic interplay on glucose metabolism and
insulin secretion control. Indeed, the search of predictive
laboratory markers is of value for clinical practice.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
ACKNOWLEDGEMENTS
This work was supported by the Government of Navarra (48/2009), the LE
Nutrition, Obesity and Health (University of Navarra LE/97) and CIBERobn/RETICS,
ISCIII initiatives. PL-L is funded by the Government of Navarra (233/2009) and ABC
and MP by the ISCIII (Sara Borrell C09/00365 and Miguel Servet schemes). This
research is collaborative study of the CIBERobn program on Fisiopatologia de la
Obesidad y la Nutricion funded by the Institute Carlos III of the Spanish Ministry of
Health, Madrid.
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