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The Effect of Glutamine Supplementation on Athletic Performance, Body Composition, and Immune Function: A Systematic Review and a Meta-Analysis of Clinical Trials

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Background & aim: This systematic review and meta-analysis of available evidence was conducted to obtain a conclusive result on the effects of glutamine supplementation on athletes. Methods: Systematic review and meta-analysis. Data related to body mass, lean body mass, body fat percentage, Vo2 max, lymphocytes, leukocytes and neutrophil counts were extracted to determine the effects of GLN on performance outcomes. Data sources: The literature search was conducted across the databases Pubmed, Scopus, ISI Web of Science, SID (Scientific Information Database) and Cochrane Central Register of Controlled Trials, covering a period up to January 2017. Eligibility criteria for selecting studies: Clinical trials evaluating glutamine supplementation outcomes on athletes aged over 18 were included. Results: A total of 47 studies were included in the systematic review, and 25 trials matched the inclusion criteria for the meta-analysis. According to the meta-analysis, glutamine has a significant effect on weight reduction (WMD = -1.36 [95% CI: -2.55 to -0.16], p = 0.02). Moreover, neutrophil numbers were reduced following glutamine intake at doses greater than 200 mg/kg body weight (WMD = -605.77 [95% CI: -1200.0 to 52.1]; P = 0.03). Also, supplementation by glutamine dipeptide resulted in higher blood glucose after exercise (WMD = 0.51 [95% CI: 0.18, 0.83] mmol/l; P = 0.002). There was no association between glutamine ingestion and other outcomes investigated. Conclusion: According to this meta-analysis, generally, glutamine supplementation has no effect on athletics immune system, aerobic performance, and body composition. However, the current study showed that glutamine resulted in greater weight reduction. In addition, the present study suggests that the efficacy of glutamine supplementation on neutrophil numbers could be affected by supplement type and dose.
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Meta-analyses
The effect of glutamine supplementation on athletic performance,
body composition, and immune function: A systematic review and a
meta-analysis of clinical trials
Q5
Q4
Amirhossein Ramezani Ahmadi
a
,
b
, Elham Rayyani
c
, Mehdi Bahreini
b
,
Anahita Mansoori
a
,
*
a
Nutrition and Metabolic Diseases Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
b
Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
c
Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
article info
Article history:
Received 2 October 2017
Accepted 2 May 2018
Keywords:
Glutamine
Immune function
Performance
Body composition
Aerobic capacity
Strength
summary
Background &aim: This systematic review and meta-analysis of available evidence was conducted to
obtain a conclusive result on the effects of glutamine supplementation on athletes.
Methods: Systematic review and meta-analysis. Data related to body mass, lean body mass, body fat
percentage, Vo2 max, lymphocytes, leukocytes and neutrophil counts were extracted to determine the
effects of GLN on performance outcomes.
Data Sources: The literature search was conducted across the databases Pubmed, Scopus, ISI Web of
Science, SID (Scientic Information Database) and Cochrane Central Register of Controlled Trials,
covering a period up to January 2017.
Eligibility Criteria for Selecting Studies: Clinical trials evaluating glutamine supplementation outcomes on
athletes aged over 18 were included.
Results: A total of 47 studies were included in the systematic review, and 25 trials matched the inclusion
criteria for the meta-analysis. According to the meta-analysis, glutamine has a signicant effect on
weight reduction (WMD ¼1.36 [95% CI: 2.55 to 0.16], p ¼0.02). Moreover, neutrophil numbers were
reduced following glutamine intake at doses greater than 200 mg/kg body weight (WMD ¼605.77
[95% CI: 1200.0 to 52.1]; P ¼0.03). Also, supplementation by glutamine dipeptide resulted in higher
blood glucose after exercise (WMD ¼0.51 [95% CI: 0.18, 0.83] mmol/l; P ¼0.002). There was no asso-
ciation between glutamine ingestion and other outcomes investigated.
Conclusion: According to this meta-analysis, generally, glutamine supplementation has no effect on
athletics immune system, aerobic performance, and body composition. However, the current study
showed that glutamine resulted in greater weight reduction. In addition, the present study suggests that
the efcacy of glutamine supplementation on neutrophil numbers could be affected by supplement type
and dose.
©2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
1. Introduction
Maintaining athletic performance is an issue constantly
considered by trainers and athletes [1]. Nowadays, athletes employ
several approaches for success in competitions, and the use of
pharmaceutical or nutritional products are the most common
among them. Some of the reasons mentioned by athletes for using
these products include: increased performance, accelerated re-
covery, and reduced muscle damage [2]. It has been frequently
suggested by various studies that nutritional supplements can in-
crease athletic performance [3]. Physical performance is highly
related to muscle function and muscle protein synthesis. Muscle
protein degradation has an important role in determining muscle
strength [4]. Amino acids are muscular building blocks and are used
*Corresponding author. Department of Nutrition, Faculty of Para-Medicine,
Ahvaz Jundishapur University of Medical Sciences, P.O.Box: 61357-15794, Ahvaz,
Khuzestan, Iran. Fax: (9861)33738253.
E-mail addresses: Mansoori_anahita@yahoo.com,Mansoori-a@ajums.ac.ir
(A. Mansoori).
Contents lists available at ScienceDirect
Clinical Nutrition
journal homepage: http://www.elsevier.com/locate/clnu
https://doi.org/10.1016/j.clnu.2018.05.0 01
0261-5614/©2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
Clinical Nutrition xxx (2018) 1e16
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as a source of energy for skeletal musculature [5]. There is scant
evidence to suggest that nonessential amino acids stimulate muscle
protein synthesis. However, glutamine (GLN), which is a nones-
sential amino acid, is different. Certain well-regarded scientic
studies have shown GLN supplementation to have specic benets,
including supporting the immune system, increasing glycogen
production, anticatabolic effects, and increasing the absorption of
water and electrolytes [6]. In laboratory animals, a direct relation-
ship has been shown between free GLN levels in muscle, and the
rate of muscle protein synthesis [7]. Sustaining a positive protein
balance and the anabolic effects of GLN supplementation may
potentially improve athletic performance (namely power, vertical
jump performance, or overall muscle strength) due to the
enhancement of muscle mass [3].
GLN is the most abundant amino acid in plasma and skeletal
muscles. About 60% of the total free amino acids in skeletal muscles
[8,9] and 20% of plasma amino acids [10] consist of GLN. This amino
acid may be used for the synthesis of other amino acids, proteins,
nucleotides and a number of other biological molecules [11].In
addition, it is essential for homeostasis (including uid balance, pH,
regulating body temperature, and heart rate), and optimal function
of some body tissues, especially the immune system and gastro-
intestinal tract [10]. This amino acid is the most important fuel
source for certain immune cells and may have a special effect on
immune stimulation [12]. For years it has been assumed that im-
mune cells use glucose as a fuel [13], but in the early 1980s, it was
found that these cells use GLN equally and in the same way as
glucose [14]. Recently, the role of GLN in immunosuppression has
become a lively topic. A decrease in plasma GLN is associated with
immune suppression after intensive exercise and in overtraining
syndrome [15]. However, there is no direct evidence demonstrating
that reduced plasma GLN following exercise or due to overtraining
syndrome is associated with impaired immune function [16]. Based
on limited studies, GLN increases the number of circulating lym-
phocytes and macrophages. Besides, a relationship has been iden-
tied between plasma GLN level and resistance to viral infection in
nonathletes [17,18].
Decreases in plasma GLN levels after prolonged exercise may be
ascribable to an increase in bodily demand and a greater GLN up-
take by tissues than normal. Plasma GLN levels can decline due to
reduced production or decrease in the release of GLN by muscles
[16]. Despite existing claims about the effects of GLN on enhancing
athletic performance and improving the immune system, the re-
sults of these studies remain conicting. This study was conducted
to evaluate the effect of GLN supplementation (in comparison to a
placebo) on athletic performance, body composition, and immune
function, in clinical trials.
2. Methods
This study follows the guidelines and PRISMA statement for
reporting systematic reviews and meta-analyses of studies. Table 1
shows the PICOS (population, intervention, comparator, outcome,
and setting) criteria used to perform the systematic review. Due to
the study type (meta-analysis and systematic review), ethical
approval was not necessary according to local legislation. The study
protocol was registered on PROSPERO (registration number:
CRD42016038438).
2.1. Literature review
Two authors (AR and ER) independently performed an extended
literature search of the following databases: Pubmed, Scopus, ISI
Web of Science, SID (Scientic Information Database) and Cochrane
Central Register of Controlled Trials and Cochrane Library database.
All studies published as original full-text articles covering a period
up to January 2017 were searched. No restriction was applied to
publication year, and all studies published in English or Persian
were included. The following medical subject heading terms and
words were used as search strategies, in all possible combinations:
glutamine, dipeptide,
L
-glutamine,
L
-Alanyl-
L
-Glutamine, sust-
amine, oral glutamine, supplement of glutamine, glutamine sup-
plementation, athletes, exercise, sport, training, athletics, body
composition, muscle mass, lean mass, lean body mass, fat mass,
body mass, weight, immune function, immune, immune response,
immunity, white blood cell, lymphocyte, leukocyte, neutrophil,
cytokine, performance, aerobic performance, anaerobic perfor-
mance, power, strength, endurance, resistance, Vo2, growth hor-
mone, GH, glucose, creatine kinase, CK, creatine phosphokinase,
phosphor-creatine kinase, CPK. For expanding the search, related
articlefunction was applied and the reference lists of selected
articles were searched for extra articles.
2.2. Study selection
Any treatment by GLN or its dipeptide (as L-Alanyl-
L
-Glutamine
or sustamine), either individually or in combination with any other
articial substance, considered as glutamine supplementation.
The following eligibility criteria were applied: a) Studies
enrolling patients over 18; b) Athletes following regular exercise
regimes; c) Controlled trials; d) GLN or L-Alanyl-
L
-Glutamine sup-
plementation; e) Trials that reported at least 1 of the outcomes
considered in the present study; f) Written in English or Persian. All
studies were considered, irrespective of whether GLN was given in
powder forms, pills or as a sports drink.
Trials with the following criteria were excluded: a) Observa-
tional studies (cohort study, caseecontrol study, ecological studies,
case reports, and case series); b) GLN supplemented in combination
with other nutrients with potential metabolic activity (for example
amino acids, nucleotides, creatine and omega-3 fatty acids); c)
Articles without full-text availability, opinion pieces, review articles
and editorials.
2.3. Data extraction
An electronic database was designed to obtain all relevant trials
data. The data were extracted separately by 2 investigators (AR and
ER), and in the event of disagreement AM cross-examined doubtful
data, with a decision being made after reaching to an agreement.
Following Information extracted from the studies: rst author,
country of origin, year of publication, study type (parallel or cross-
over), gender, blinding, GLN dosage, administration method, period
of supplementation, the regimen of the control groups, type of
sport/exercise, and various outcome measurements.
The primary purpose of this systematic review and meta-
analysis was to evaluate if GLN supplementation could affect ath-
letic performance, immune function and body composition based
Table 1
PICOS (population, intervention, comparator, outcome, and setting) criteria used to
perform the systematic review.
PICOS Criteria
Population Healthy active subjects
Intervention Glutamine supplementation
Comparator Placebo group
Outcome Immune function; Athletic
performance; Body composition;
Blood markers (growth hormone,
blood glucose, and Creatine kinase)
Setting Clinical trials
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on clinical trials conducted so far. All related studies have been
reviewed, and the following were the most frequent measurements
used for conducting the meta-analysis. Data related to body weight,
lean body mass, and body fat percentage were extracted before and
after supplementation for evaluating the effects of GLN supple-
mentation on body composition. For athletic aerobic performance,
Vo2 max data were extracted. Data related to lymphocyte, leuko-
cyte, and neutrophil counts was used for determining the effects of
GLN on immune function. As a secondary endpoint of the analysis,
the effects of GLN on concentrations of GH, CK and blood glucose
was considered, which are indirectly related to sport performance
and body composition. The quality of the studies was evaluated by
2 separate reviewers (AR and ER) based on the Jadad score [19].
2.4. Statistical analysis
The effect size, as estimated by the mean difference (MD), was
used to perform the xed method meta-analysis. A random-effects
meta-analysis was carried out for each measurement where there
was a signicant heterogeneity between studies [20]. Heteroge-
neity was assessed using the I
2
index, and by testing the null hy-
pothesis that all studies reveal a common effect size. Heterogeneity
was considered low if I
2
<30%, moderate if I
2
¼30e75%, and high if
I
2
>75% [21]. To identify the potential sources of heterogeneity,
stratied analyses were performed according to the following in-
dicators: GLN dosage (0.2 g/kg/day or <0.2 g/kg/day), duration of
GLN supplement (acute or chronic), supplement type (glutamine or
sustamine), and study quality (low or high). Acute supplementation
included interventions that were conducted in a single day.
Moreover, studies classied according to sport type into the
following groups: Endurance and team sports (e.g. soccer, track and
eld, altitude training, Repeated High-Intensity Endurance Test,
rowing, cycling, running, and military training); Wight class and
aesthetic sports (e.g. wrestling, judo, gymnastics and Resistance
training). For all the analyses, the presence of a different effect
between subgroups was tested for.
Funnel plots were used to visually inspect for the presence of
publication bias. In addition, for further investigation of publication
bias, Begg's rank correlation and Egger's linear regression tests
were used. All analyses were carried out using Stata, version 12 SE
(Stata Crop, College Station, TX, USA). P-values <0.05 were
considered statistically signicant.
3. Results
3.1. Study characteristics
As shown in Fig. 1 the early electronic search resulted in 1066
studies, after duplicate removal. Following a title and abstract
screen, 996 studies were excluded due to reporting unrelated data,
including animal subjects, being review articles, and being written
in neither English nor Persian. Overall, 68 studies were evaluated
Fig. 1. Flow diagram of literature search according to the PRISMA statement.
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immune function: A systematic review and a meta-analysis of clinical trials, Clinical Nutrition (2018), https://doi.org/10.1016/j.clnu.2018.05.001
for eligibility, and 21 studies were excluded for the following rea-
sons: a) Used a combination preparation with other ergogenic aids
or amino acids [5,15,22e30]; b) Did not report measurements
related to the aims of this study [31e39]; and c) Were not per-
formed on human subjects [40]. From 47 trials included in the
systematic review, 25 of them met the inclusion criteria for meta-
analysis. Table 2 summarizes the information on all the trials
included in the systematic review. A total of 29 studies (62%)
employed a parallel study design, whereas 18 studies (38%) used a
cross-over design. Most studies (n ¼37) were conducted on male
subjects, 8 trials involved both male and female participants, and 2
recruited only females. The majority of the trials tested the effects
of GLN in acute supplementation (n ¼23), while the duration of
intervention in 16 studies was fewer than 4 weeks, and in 7 trials
was longer than 4 weeks. Dosages of GLN supplements are not
directly comparable, as in some studies authors adjusted the sup-
plement according to participants' weight, while in others there
was no difference in dosage according to weight. Based on the Jadad
score, in more than half of the trials (n ¼27), the study quality was
high, but 20 trials received a poor score due to a lack of randomi-
zation or double-blinding.
4. Glutamine supplementation and immune function
4.1. Qualitative synthesis
Overall, 20 studies considered the effect of GLN supplementa-
tion on immune function [1,12,14,16,18,41e55]. One study showed a
signicant reduction in the incidence of infection following 7 days
of GLN ingestion in athletes [18].
One study showed that the ratio of CD4þhelper/CD8þsup-
pressor cells signicantly decreased in the placebo group than in
the GLN group [41]. On the other hand, in one study, CD8þ
reduction due to GLN supplementation resulted in a signicant
increase in the ratio of CD4þ/CD8þ, while this ratio remained
unchanged in the control group [54]. However, in 4 studies, the
numbers of CD4þand CD8þwere not different between the GLN
group and the placebo group [14,42,43,48]. In one study, the per-
centage of T-cells was signicantly greater in the GLN group
exclusively 16 h post-exercise, in comparison to the placebo [14].
Also, a study showed a signicant elevation inpost-training Natural
Killer (NK) activity in athletes who received GLN supplementation
[54]. However, three studies found no effect of GLN supplementa-
tion on NK cell activity [14,43,44].
One study that evaluated the effect of GLN supplementation on
B cell counts found no difference between the experimental and
control groups [14]. The effect of GLN supplementation on the
change of salivary immunoglobulin A (s-IgA) was not signicant in
3 studies [1,12,47]. Also, some studies found no difference between
the GLN group and placebo in plasma levels of Ig M [52,54], IgA
[50,52,54] and IgG [50,52,54]. However, one study reported that
nasal IgA was greater in athletes receiving GLN compared to the
placebo [47].
In 10 studies that considered the effect of GLN on total leukocyte
counts, 8 studies found there was no signicant difference in total
leukocyte numbers after GLN supplementation compared to a
placebo [14,16,41,43,45,48e50]. Two of the studies indicated that
leukocyte numbers considerably increased following GLN intake,
compared to the placebo [51,52]. Nine studies that examined
lymphocyte numbers reported no difference between the GLN and
the placebo group [14,16,41e45,48,49]. In six studies, GLN supple-
mentation did not affect the change in neutrophil numbers
[16,42,43,45,48,49]. One study showed that neutrophil numbers
were less enhanced in the GLN group, compared to the placebo
[44]. Sasaki and colleagues found that after one week (but not two
weeks) following GLN supplementation, neutrophil numbers
increased signicantly after exercise, although in the placebo group
there was a little reduction in neutrophil numbers compared to
pre-exercise [50]. Also, another study reported greater increases in
neutrophil numbers in the GLN group [52]. Three studies reported
that GLN supplementation had no effect on monocyte numbers
[43,48,49].
Also, according to studies that investigated the link between of
GLN supplementation and athletes' immune function, there was no
difference in the plasma concentration of complements (C3, C4
[50,52] and C5a [14]), C-reactive protein (CRP) [14], neopterine [14],
Interleukin-6 (IL-6) [14], interferon-ɣ(IFɣ)[14], concanavalin A
(ConA) stimulated proliferative response [43], lymphokine acti-
vated killer (LAK) [42e44], phytohaemagglutinin stimulated
lymphocyte (PHA) proliferative response [42,43], and phagocyte
activity [50,52] between the GLN and placebo groups. However, one
study showed a greater plasma level of IL-6 immediately after ex-
ercise, in the GLN group compared to the placebo [46]. Moreover,
two studies showed that the peripheral blood mononuclear cells
(PBMC) level of I
k
B
a
(nuclear factor of kappa light polypeptide gene
enhancer in B-cells inhibitor, alpha) increased in response to ex-
ercise in the GLN group [53,55]. Two studies also indicated a greater
heat shock protein 70 (HSP70) expression in the GLN group when
compared to a placebo [53,55]. Also, Zuhl and colleagues reported
that plasma levels of tumor necrosis factor alpha (TNF-
a
)were
signicantly lower in the GLN group compared to placebo [55].
4.2. Quantitative synthesis
Nine trials, including 173 subjects (n ¼89 treated and 84 con-
trols) provided data on leukocyte numbers for meta-analysis
[14,16,41,44,45,48,49,51,52]. Among these, 4 trials [14,16,41,44]
were acute and 5 were longer-term intervention [45,48,49,51,52].
As shown in Fig. 2a, GLN supplementation did not reveal a signif-
icant leukocyte-increasing effect, compared to placebo (mean
difference ¼198.07 [95% CI: 749.1, 1145.3] n/
m
l; P ¼0.68). Mod-
erate heterogeneity was observed among the studies (I
2
¼64.5,
P¼0.004). The subgroup analysis of study duration (acute or
chronic supplementation), quality (high or low) and supplement
dose (<200 mg/kg body weight/day or 200 mg/kg body weight/
day) shows that heterogeneity was signicant in trials with chronic
intervention (n ¼5, I
2
¼79.6, P ¼0.001), with supplement dose
above 200 mg/kg BW (n ¼4, I
2
¼83.4, P <0.001), in weight class
and aesthetic athletes (n ¼4, I
2
¼82.9, P ¼0.001), and in low
quality studies (n ¼3, I
2
¼81.6, P ¼0.004). Also, subgroup analysis
suggested that leukocyte numbers reduced in acute intervention
and increased in chronic intervention, but none of them were sig-
nicant statistically (Table 3). Sensitivity analysis suggests no dif-
ference in the results, following the exclusion any of the trials. A
funnel plot (Fig. 3A) demonstrated no publication bias of trials in
investigating the effect of GLN supplementation on leukocyte
numbers (Egger's test P ¼0.95; Begg's test P ¼0.53).
Overall, 8 studies provided enough data regarding the effect of
GLN supplementation on neutrophils numbers (n ¼84 treated and
81 controls). According to the meta-analysis, GLN supplementation
did not signicantly affect the neutrophils numbers, compared to
the placebo group (mean difference ¼112.70 [95% CI: 389.7,
164.3] n/
m
l; P ¼0.42; Fig. 2b). There was low heterogeneity be-
tween studies (I
2
¼24.6, P ¼0.23). Five studies conducted in
chronic duration and 3 were acute intervention. The subgroup
analysis of study duration (acute or chronic) showed that there was
no signicant difference between acute (P ¼0.58) or chronic
(p ¼0.47) supplementation of GLN on neutrophil counts. Similar
results were seen for two groups of sport type. Supplement doses of
more than 0.2 gr/kg BW GLN resulted in a signicant decline in
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Table 2
Characteristics of the included trials.
Author (year) Country Study design Gender Blindness Quality No. of
population
No. of
intervention/
placebo
Intervention
duration
Supplement type Placebo type Supplement dose Outcomes Sport type
Castell, L. M. et al.
(1996) [18]
Belgium Parallel Male and
female
Double High 151 72/79 Acute GLN + mineral
water
Maltodextrin 5 gr Immune function ultra-marathon or
marathon runners,
Rowers
Castell, L. M. et al.
(1997) [14]
Belgium Parallel Male and
female
Double High 18 10/8 Acute GLN + mineral
water
Maltodextrin 100 mg/kg Immune function Ultra-marathon or
marathon runners,
rowers
Castell, L. M. et al.
(1997) [41]
Belgium Parallel Male Double High 18 10/8 Acute GLN + water Maltodextrin 5 gr Immune function Marathon runners
Rohde, T. et al.
(1998) [42]
Denmark Parallel Male Single Low 16 9/7 Acute GLN CHO-free
lemonade
400 mg/kg Immune function Marathon runners
Rohde, T. et al.
(1998) [43]
Denmark Cross-over Male Single Low 8 8/8 Acute GLN CHO-free
lemonade
900 mg/kg Immune function e
Haub, M. D. et al.
(1998) [56]
USA Cross-over Male Double High 10 10/10 Acute GLN Sucrose 30 mg/kg/day Performance physically active
subjects
Walsh, N. P. et al.
(2000) [16]
England Cross-over Male Single Low 7 7/7 Acute GLN Sugar-free
lemon drink
42 gr Plasma glucose,
Immune function,
performance
Cycle
Akbarnejad, A. et al.
(2001) [10]
Iran Parallel Male Single Low 21 7/7 1 week GLN Did not intake
anything
300 mg/kg/day Performance Wrestling
Candow, D. G. et al.
(2001) [57]
Canada Parallel Male and
female
Double High 31 17/14 6 weeks GLN Maltodextrin 900 mg/kg of lean
body mass/day
Body composition Resistance
training 2e4
times a week
Krzywkowski, K. et
al. (2001) [44]
Denmark Cross-over Male Double High 10 10/10 Acute GLN Maltodextrin 17.5 gr Immune function,
Plasma glucose
Growth hormone
Elite athletes
Krzywkowski, K. et
al. (2001) [12]
Denmark Cross-over Male Double High 11 11/11 Acute GLN Maltodextrin 17.5 gr Immune function endurance
trained sportsmen
Bruce, M. et al.
(2001) [58]
England Cross-over Male Double Low 7 7/7 Acute GLN + Articially
sweetened beverage
Articially
sweetened
beverage
125 mg/kg Performance,
Glucose
Cyclist
Banaeifar, A. (2003)
[45]
Iran Parallel Male Single Low 20 10/10 1 month GLN Lemonade 50 mg/kg/day Immune function Wrestler
Lehmkuhl, M. et al.
(2003) [3]
USA Parallel Male and
female
Double High 29 10/9 8 weeks Creatine
monohydrate + GLN
Creatine
monohydrate
4 gr/day Body composition Track &eld
Finn, K. J. et al.
(2003) [59]
USA Parallel Male Double High 18 9/9 12 days GLN + Articially
sweetened beverage
Articially
sweetened
beverage
350 mg/kg/day Body composition Wrestler
Hiscock, N. et al.
(2003) [46]
Denmark Cross-over Male Double Low 8 8/8 Acute GLN Maltodextrin 3.5 gr Immune function,
Plasma glucose
Healthy trained
Krieger, J. W. et al.
(2004) [47]
USA Parallel Male and
female
Double High 13 6/7 2 weeks GLN Sugar-free
lemon drink
100 mg/kg/day Immune function,
performance
Runner
Marwood, S. et al.
(2007) [60]
England Cross-over Male Single Low 8 8/8 2 days GLN Sugar-free
lemon drink
125 mg/kg/day performance Cyclist
Dabidi Roshan, V. et
al. [1]
Iran Parallel Male Double High 23 12/11 Acute GLN Sugar-free
lemon drink
100 mg/kg Immune function Students
Alijani, E. et al.
(2008) [48]
Iran Parallel Female Double High 30 10/10 Acute GLN Maltodextrin 14 gr Immune function Athletics
Ziaee, V. et al.
(2008) [49]
Iran Parallel Male Single Low 21 7/7 1 week Creatine
monohydrate + GLN
Creatine
monohydrate
300 mg/kg/day Immune function Wrestler
Favano, A. et al.
(2008) [61]
Brazil Parallel Male Double High 16 9/7 Acute GLN Maltodextrin 3.5 gr Performance soccer
Hoffman J. R. et al.
(2010) [62]
USA Cross-over Male Single Low 10 10/10 Acute Sustamine Water 200 mg/kg
50 mg/kg
Blood factors Physically active
subjects
(continued on next page)
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Table 2 (continued )
Author (year) Country Study design Gender Blindness Quality No. of
population
No. of
intervention/
placebo
Intervention
duration
Supplement type Placebo type Supplement dose Outcomes Sport type
Ghanbarzadeh, M.
et al. (2011) [63]
Iran Parallel Male Single Low 20 10/10 8 weeks GLN + water + sugar Water + sugar 100 mg/kg/day Performance,
Body composition
Soccer
Ghasemi, A. et al.
(2011) [64]
Iran Parallel Male Single Low 10 5/5 4 weeks GLN + water Water + glucose 28 gr. Twice/week Blood factors Student athletes
Street, B. (2011)
[65]
England Parallel Male Single Low 15 7/8 4 days GLN Maltodextrin 300 mg/kg/day Performance,
Blood factors
drop jumps
(eccentric exercise)
Hoffman J. R. et al.
(2012) [66]
USA Cross-over Female Double Low 10 10/10 Acute Sustamine Water 1 gr/day
2 gr/day
Performance Basketball
Hakimi, M. et al.
(2012) [67]
Iran Parallel Male Double High 30 15/15 8 weeks GLN Starch 350 mg/kg/day Blood factors,
Body composition
Nonathlete healthy
young male students
Rowlands, D. S. et
al. (2012) [68]
New Zealand Cross-over Male Double High 8 8/8 Acute GLN Glucose, sodium
citrate,
orange avor,
and ltered water
9.9 gr Performance,
Blood factors
cycle &triathlete
Karami, S. et al.
(2013) [69]
Iran Parallel Male Double High 14 7/7 Acute GLN Not mentioned 500 mg/kg Blood factors Soccer
Sasaki, E. et al.
(2013) [50]
Japan Parallel Male Single Low 26 13/13 2 weeks GLN Not mentioned 3 gr/day Blood factors,
Immune function
Judo
Khorshidi-Hosseini,
m. et al. (2013)
[70]
Iran Parallel Male Double High 14 7/7 Acute GLN +
Sweetener +
water
Sweetener + water 250 mg/kg/day Performance physical education
students
Piattoly, T. et al.
(2013) [6]
USA Parallel Male Double High 12 6/6 6 days GLN Carbohydrate 300 mg/kg/day Performance Cyclist
Abbasalipour, M. et
al. (2014) [51]
Iran Parallel Male Double High 14 7/7 15 days GLN Not mentioned 300 mg/kg/day Immune function Elite wrestler
Nomura, T. et al.
(2014) [52]
Japan Parallel Male Single Low 35 18/17 9 days GLN Not mentioned 6 gr/day Immune function,
Body composition,
CK,
Judo
da Silveira, C. L. et
al. (2014) [71]
Brazil Parallel Male Double High 32 10/12 12 weeks GLN Corn our 300 mg/kg/day Performance Military police
ofcers
Caris, A.V. et al.
(2014) [72]
Brazil Cross-over Male Double High 9 9/9 3 weeks GLN Corn starch +
lactose
20 gr/day Blood factors Colorado Altitude
Training
Koo, G. H. et al.
(2014) [73]
Korea Cross-over Male Single Low 5 5/5 1 weeks GLN Not mentioned 6 gr/day Blood factors Elite rowing athletes
Rahmani-Nia, F. et
al. (2014) [74,75]
Iran Parallel Male Double High 17 9/8 2 days GLN Maltodextrin 100 mg/kg/day Blood factors,
performance
Untrained healthy
Pruna, G. J. et al.
(2014)
USA Cross-over Male Double High 12 12/12 Acute Sustamine Electrolyte drink
(Cho, Na, K)
0.6 gr
1gr
Performance Endurance runners
Zuhl, M. et al.
(2014) [53]
USA Cross-over Male and
female
Double Low 8 8/8 2 weeks GLN Sugar-free
lemon drink
900 mg/kg of
fat-free mass
Immune function University student
athletes
Legault, Z. et al.
(2014) [76]
Canada Cross-over Male and
female
Double High 16 16/16 3 days GLN Maltodextrin 300 mg/kg/day Performance Eccentric exercise
Zuhl, M. et al.
(2015) [55]
USA Cross-over Male and
female
Double Low 7 7/7 Acute GLN Sugar-free
lemon drink
900 mg/kg of
fat-free mass
Immune function Trained endurance
athletes
Mccormack, W. P.
et al. (2015) [77]
USA Cross-over Male Double High 12 12/12 Acute Sustamine Sports drink
(Cho, Na, K)
300 mg/500 ml
1 g/500 ml (250 ml
every 15 min)
Blood factors Endurance runners
Song, Q. H. et al.
(2015) [54]
China Parallel Male Single Low 24 12/12 6 weeks GLN Not mentioned 10 gr/day Immune function Swimmers
Najarzadeh, A. et al.
[78]
Iran Parallel Male Double High 80 40/40 Acute GLN Maltodextrin 100 mg/kg BW CK University student
athletes
Nakhostin-Roohi, B.
et al. [79]
Iran Parallel Male Double High 19 9/10 1 Week GLN + Sweetener +
water
Sweetener + water 150 mg/kg/day CK Young active
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Fig. 2. Forest plot detailing weighted mean difference and 95% condence intervals for the impact of GLN supplementation on immune function. A, leukocyte; B,
lymphocyte; C, neutrophil. Square size shows the weight of study in pooled analysis and horizontal bars reecting the 95% condence interval.
A.R. Ahmadi et al. / Clinical Nutrition xxx (2018) 1e16 7
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neutrophil numbers (n ¼3, mean difference ¼605.77 [95%
CI: 1200.0, 52.1] n/
m
l; P ¼0.03). Sensitivity analysis did not pro-
vide any further information. The funnel plot did not show any
publication bias between trials (Egger's test P ¼0.36; Begg's test
P¼0.80; Fig. 3B).
Eight studies reported the effect of GLN supplementation on
lymphocyte numbers. Five studies were acute duration and 3 were
chronic. The meta-analysis on the mean change of lymphocyte
numbers after GLN or placebo supplementation in plasma was
conducted on 141 subjects (73 treatments and 67 placeboes). It was
found that GLN supplementation did not signicantly change
lymphocyte numbers compared to placebo (mean
difference ¼65.71 [95% CI: 275.7, 144.2] n/
m
l; P ¼0.54; Fig. 2c).
Heterogeneity was not obvious among studies (I
2
¼0.0, P ¼0.71).
The effect sizes were constant in the sensitivity analysis. There were
no any differences between doses 0.2 gr/kg/day and <0.2 gr/kg/
day of GLN on lymphocyte numbers. Similarly, the lymphocyte
numbers did not signicantly change with GLN supplementation in
either the subgroups of study duration (acute or chronic supple-
mentation), sport type (endurance and team sports or weight class
and aesthetics), and study quality (high or low). For trials consid-
ering lymphocyte numbers, neither Begg's (P ¼0.57) and Egger's
test (P ¼0.64), nor a visual inspection of the funnel plot showed any
publication bias (Fig. 3C).
Table 3
Overall estimates of meta-analysis on the effect of glutamine on study outcomes.
Q
6
Outcomes Subgroups No. of trials References WMD (95% CI) P-value I
2
(%) P-value for
heterogeneity
Immune function
Leukocyte (n/
m
l) 9 [14,16,41,44,45,48,49,51,52] 198.07 (749.1, 1145.3) 0.68 64.5 0.004
Study duration Acute 4 [14,16,41,44] 486.94 (2300.1, 1375.2) 0.60 0.0 0.48
Chronic 5 [45,48,49,51,52] 181.33 (194.6, 557.3) 0.34 79.6 0.001
Supplement dose <200 mg/kg BW 5 [14,16,41,45,52] 59.25 (336.5, 455.1) 0.76 0.0 0.60
200 mg/kg BW 4 [44,48,49,51] 780.32 (230.2, 1790.9) 0.13 83.4 <0.001
quality Low 3 [41,44,51] 1794.90 (542.7, 3047.1) 0.005 81.6 0.004
High 6 [14,16,45,48,49,52] 0.37 (386.0, 385.26) 0.99 0.0 048
Sport type Endurance and team 5 [14,16,41,44,48] 839.29 (2200.0, 511.01) 0.38 0.0 0.60
Weight class and aesthetic 4 [45,49,51,52] 653.85 (595.79, 1903.50) 0.50 82.9 0.001
Neutrophil (n/
m
l) 8 [16,42,44,45,48e50,52] 112.70 (389.7, 164.3) 0.42 24.6 0.23
Study duration Acute 3 [16,42,44] 430.79 (2000.0, 1111.8) 0.58 0.0 0.41
Chronic 5 [45,48e50,52] 102.10 (383.6, 179.4) 0.47 45.6 0.11
Supplement dose <200 mg/kg BW 5 [16,42,45,50,52] 51.91 (268.0, 371.8) 0.75 3.2 0.38
200 mg/kg BW 3 [44,48,49] 605.77 (1200.0,-52.1) 0.03 0.0 0.57
Sport type Endurance and team 4 [16,42,44,48] 644.49 (2100.0, 793.05) 0.38 0.0 0.50
Weight class and aesthetic 4 [45,49,50,52] 154.94 (612.21, 302.31) 0.52 53.3 0.09
Lymphocyte (n/
m
l) 8 [14,16,41,42,44,45,48,49] 65.71 (275.7, 144.2) 0.54 0.0 0.71
Study duration Acute 5 [14,16,41,42,44] 3.31 (358.5, 351.8) 0.98 0.0 0.43
Chronic 3 [45,48,49] 99.22 (359.5, 161.1) 0.45 0.0 0.73
Supplement dose <200 mg/kg BW 5 [14,16,41,42,45] 21.11 (253.7, 211.5) 0.85 0.0 0.44
200 mg/kg BW 3 [44,48,49] 262.2 (750.4, 225.9) 0.29 0.0 0.94
Quality Low 2 [41,44] 260.06 (811.5, 291.35) 0.35 0.0 0.88
High 6 [14,16,42,45,48,49] 32.75 (259.8, 194.3) 0.77 0.0 0.54
Sport type Endurance and team 6 [14,16,41,42,44,48] 0.71 (354.93, 353.51) 0.99 0.0 0.57
Weight class and aesthetic 2 [45,49] 100.92 (361.62, 159.77) 0.44 0.0 0.45
Body composition
Body mass 5 [3,52,59,63,67] 1.36 (2.55, 0.17) 0.02 0.0 0.93
Supplement dose <200 mg/kg BW 3 [3,52,63] 1.45 (2.67, 0.23) 0.02 0.0 0.89
200 mg/kg BW 2 [59,67] 0.95 (5.06, 6.72) 0.78 0.0 0.82
Quality Low 2 [52,63] 1.47 (2.69, 0.24) 0.02 0.0 0.78
High 3 [3,59,67] 0.95 (4.63, 6.54) 0.73 0.0 0.96
Sport type Endurance and team 2 [3,63] 1.47 (2.69, 0.24) 0.01 0.0 0.69
Weight class and aesthetic 3 [52,59,67] 0.63 (4.52, 5.79) 0.81 0.0 0.96
Fat mass 5 [3,52,59,63,67] 1.01 (0.19, 2.22) 0.09 0.0 0.58
Supplement dose <200 mg/kg BW 3 [3,52,63] 1.61 (0.09, 3.12) 0.03 0.0 0.55
200 mg/kg BW 2 [59,67] 0.01 (1.99, 1.97) 0.99 0.0 0.81
Quality Low 2 [52,63] 1.64 (0.11, 3.17) 0.03 7.3 0.29
High 3 [3,59,67] 0.02 (1.98, 1.94) 0.98 0.0 0.97
Sport type Endurance and team 2 [3,63] 1.96 (0.30, 3.63) 0.02 0.0 0.69
Weight class and aesthetic 3 [52,59,67] 0.03 (1.78, 1.71) 0.96 0.0 0.97
Lean body mass 5 [3,52,57,59,67] 0.38 (2.94, 3.71) 0.81 0.0 0.99
Supplement dose <200 mg/kg BW 2 [3,52] 0.002 (4.76, 4.76) 0.99 0.0 0.77
200 mg/kg BW 3 [57,59,67] 0.77 (3.75, 5.29) 0.73 0.0 0.94
Aerobic capacity
Vo2
max
(ml/kg/min) 3 [10,63,71] 0.96 (5.1, 3.2) 0.65 68.7 0.04
Blood factors
Glucose (mmol/l) 8 [16,44,62,69,72,77] 0.27 (0.24, 0.78) 0.29 88.5 <0.001
Quality Low 3 [16,62] 0.43 (0.10, 0.96) 0.11 31.0 0.23
High 5 [44,69,72,77] 0.46 (0.55, 0.36) <0.001 91.6 <0.001
Supplement dose <200 mg/kg BW 3 [62,77] 0.45 (0.11, 0.78) 0.008 0.0 0.95
200 mg/kg BW 5 [16,44,62,69,72] 0.51 (0.61, 0.41) <0.001 87.3 <0.001
Supplement type Glutamine 4 [16,44,69,72] 0.01 (0.65, 0.57) 0.96 87.0 <0.001
Sustamine 4 [62,77] 0.51 (0.18, 0.83) 0.002 0.0 0.52
CK (UI/l) 3 [50,52,73] 20.29 (86.55, 45.97) 0.54 0.0 0.67
GH (ng/l) 3 [44,64,67] 0.17 (1.50, 1.85) 0.83 64.2 0.06
WMD, weight mean difference; BW, body weight; CK, creatine kinase; GH, growth hormone.
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5. Glutamine supplementation and body composition
5.1. Qualitative synthesis
In total, 6 studies [3,52,57,59,63,67] investigated the results of
GLN supplementation on body composition. One of these studies
examined the effect of a mixture of GLN and creatine on body
composition, which showed that in both the creatine mono-
hydrate and creatine monohydrate plus GLN groups, body mass
and LBM (measured by skinfolds) increased more than in the
placebo group (p ¼0.016). Fat mass and percentage of body fat
presented no signicant changes over time [3]. Nomura and col-
leagues found that post-practice body weight decreased signi-
cantly, pre- and post-intervention for both the GLN and the
placebo groups (p <0.01 for all) [52].Candowandcolleagues
found GLN supplementation during 6 weeks of resistance training
had no signicant effect on body composition [57].Also,a12-day
period of intervention resulted in a remarkable loss of body
weight (p <0.001), lean body mass (p <0.001), and fat mass
(p <0.001) in both intervention and control groups, but there
were no signicant differences between two groups [59].Two
studies showed that body weight and lean body mass signicantly
increased following 8 weeks of GLN supplementation, and a
decrease in body fat percentage was observed during this period
[63,67].
5.2. Quantitative synthesis
Overall, 6 studies provided enough data to evaluate the effect of
GLN supplementation on body composition. The duration of all
these studies was more than a day and they were chronic studies.
Five studies including a total of 122 subjects (62 treated and 60
controls) investigated the effect of GLN supplementation on fat
mass and body weight. In addition, 5 studies (including 69 subjects
in the GLN group and 64 controls), examined the effects of GLN on
lean mass. These studies suggested an inverse association between
GLN consumption and body weight (mean difference ¼1.36 [95%
CI: 2.55, 0.16] kg, p ¼0.02, Fig. 4a). There was no heterogeneity
among the studies (I
2
¼0.0%, p ¼0.93). Sensitivity analysis showed
that this signicant relationship disappears (mean
difference ¼0.75 [95% CI: 4.19, 5.70] kg) by eliminating the study
of Ghanbarzadeh et al. [63].
No association was observed between GLN consumption and fat
(Fig. 4b) or lean mass (Fig. 4c) (mean difference ¼1.01 [95%
CI: 0.19, 2.22] kg, p ¼0.09, and mean difference ¼0.38 [95%
CI: 2.94, 3.71] kg, p ¼0.81, respectively), and there was no het-
erogeneity between studies (I
2
¼0.0%, p ¼0.58, and I
2
¼0.0%,
p¼0.99, respectively). According to the subgroup analysis, a sig-
nicant increase in body fat mass was observed in low quality
studies (n ¼2, mean difference ¼1.64 [95% CI: 0.11, 3.17] kg,
p¼0.03). Similar results were also found in studies which sup-
plemented GLN at doses lower than 0.2 gr/kg BW (n ¼3, mean
difference ¼1.61 [95% CI: 0.09, 3.12] kg, p ¼0.04) and endurance
and team sport type (n ¼3, mean difference ¼1.96 [95% CI: 0.30,
3.63] kg, p ¼0.02). Although it appears that only one study
returned these results [63], a sensitivity analysis did not conrm
this. There were no signicant differences in the effects of GLN
intake on lean body mass, after dividing the groups by study quality
and supplement dose. Sensitivity analysis did not show any change
in the results related to fat mass and lean body mass.
Fig. 3. Funnel plots detailing publication bias in the studies selected for analysis. A, total leukocyte counts; B, lymphocyte counts; C, neutrophil counts. WMD: Weight Mean
difference. Visual inspection of funnel plots indicating that there is no publication bias among studies.
A.R. Ahmadi et al. / Clinical Nutrition xxx (2018) 1e16 9
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Please cite this article in press as: Ahmadi AR, et al., The effect of glutamine supplementation on athletic performance, body composition, and
immune function: A systematic review and a meta-analysis of clinical trials, Clinical Nutrition (2018), https://doi.org/10.1016/j.clnu.2018.05.001
6. Glutamine supplementation and athletic performance
6.1. Qualitative synthesis
According to our systematic review, 16 trials investigated the
effects of GLN supplementation on different aspects of athletic
performance.
Two studies reported that GLN supplementation had no effect
on aerobic capacity, as evaluated by VO
2
max, compared to placebo
groups [10,71]. One study concluded that GLN supplementation did
not affect oxygen consumption and energy expenditure during
exercise. GLN also had a trivial effect on exogenous glucose
oxidation rate, relative to a control group [68]. In addition, two
studies found that pulmonary oxygen consumption (VO
2
), mean
Fig. 4. Forest plot detailing weighted mean difference and 95% condence intervals for the impact of GLN supplementation on body composition. A, body weight; B, fat
mass; C, lean body mass. Square size shows the weight of study in pooled analysis and horizontal bars reecting the 95% condence interval.
A.R. Ahmadi et al. / Clinical Nutrition xxx (2018) 1e1610
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immune function: A systematic review and a meta-analysis of clinical trials, Clinical Nutrition (2018), https://doi.org/10.1016/j.clnu.2018.05.001
response time of % hemoglobin (Hb; as an indicative of muscle
deoxygenation kinetics), respiratory exchange ratio, and expired
ventilation were not different between the GLN and placebo groups
[58,60]. However, in one of these studies, the mean response time
of VO
2
was faster in the GLN group. Moreover, taking GLN during
the early phase of exercise increased muscle oxygen consumption,
%Hb and oxidative metabolism [60]. One study also showed that
GLN supplementation had a signicant enhancement effect on
aerobic power (VO
2
max) [63]. In three studies no signicant dif-
ference was observed between GLN and placebo groups in heart
rate measurements [47,58,66].
Three studies found a signicant increase in peak, minimum and
mean anaerobic power (Rast or Wingate test) following GLN sup-
plementation compared to a placebo [6,63,70]. On the other hand,
in one study the authors did not nd any signicant relationship
between GLN supplementation and improvement in anaerobic
performance (measured by shuttle run test), upper limb muscle
strength (evaluated by pushups), lower limb muscle strength
(evaluated by horizontal jump), exibility (determined by the sit
and reach test), and abdominal muscle endurance (determined by
sit-up test) [71]. According to one study, the lactate threshold and
lactate tolerance did not change following GLN supplementation, in
comparison with placebo groups [10].
A study carried out on basketball players showed that GLN
supplementation resulted in a signicant improvement in a
shooting drill, shooting performance and visual reaction time,
although there was no difference between trials in lower body
reaction, motor response, vertical jump power and player loads. In
this study, low and high doses of GLN had a similar effect [66].In
contrast, another study that compared rehydration with two doses
of L-Alanyl-
L
-Glutamine (low dose and high dose) and a simple
electrolyte drink, indicated that visual, physical and motor reaction
times were likely to be faster with a low dose of L-Alanyl-
L
-Gluta-
mine than in other trials. Also, this study showed a possible
advantage for high doses of supplements in terms of the number of
successful shots. With both low and high doses of supplementation,
an improvement in lower body response time was observed. There
was no difference in cognitive performance between trials [80].
One study suggested a signicantly greater peak torque (as an
indicator of strength) over 96 h after exercise, for the GLN group
compared to a placebo group [65]. Another study found that GLN
supplementation resulted in higher peak torque post-exercise only
in male gender [76]. Two studies showed that the rating of
perceived exertion (RPE) inclined to be greater in the GLN group
compared to the placebo [16,68].
One study showed that GLN supplementation caused an
improvement in total distance covered and duration of tolerance
[61]. Two other studies showed that subjects who received GLN
supplements experienced less fatigue than the placebo group and
that the mean time until fatigue or exhaustion was longer for
athletes in the GLN group [6,61]. In contrast, one study reported a
small increase in leg muscle tiredness with GLN supplementation,
compared to glucose or a placebo [68]. Additionally, two studies
indicated that GLN makes no signicant difference in fatigue
perception in comparison to placebo [56,70].
One study considering the effect of GLN supplementation on
surface electromyography (sEMG; an indicator of muscle fatigue
and muscle damage) concluded that there was no difference be-
tween GLN and placebo groups, with sEMG decreasing signicantly
after exercise in both groups [74].
In one study, GLN supplementation did not affect the timing and
magnitude of the soreness, although it diminished soreness more
rapidly than in the control group [65]. Also, Rahmani-Nia and col-
leagues did not observe any effect of GLN supplementation on
muscle soreness compared to a placebo [74]. In another study, a
lower rate of knee extensor and muscle soreness was noted in the
GLN group compared to the placebo group [76].
6.2. Quantitative synthesis
Overall, only 3 studies (56 subjects; 27 in treatment and 29 in
the placebo group) remained to be included in the meta-analysis,
according to the inclusion criteria. It was found that GLN supple-
mentation had no signicant effect on Vo2max compared to pla-
cebo (mean difference ¼0.96 [95% CI: 5.1, 3.2] ml/kg/min;
P¼0.65; Fig. 5a). There was moderate heterogeneity among studies
(I
2
¼68.7, P ¼0.04). Sensitivity analysis did not give any further
information.
7. Glutamine supplementation and blood markers
7.1. Qualitative synthesis
Six trials studied the effect of GLN supplementation on blood
glucose, and none of them found signicant associations
[16,44,62,69,72,77].
Four studies were found relevant to the outcomes of GLN sup-
plementation on growth hormone levels. Three of these studies
found no effect of GLN supplementation on growth hormone
[44,62,64], but Hakimi and colleagues [67] showed 0.35 gr/kg/day
GLN over 8 weeks caused signicantly greater increases in blood
GH in the GLN group compared to the placebo group.
Among 8 studies that investigated the effect of GLN supple-
mentation on blood CK, one study showed serum CK decreased 1
week after the intervention, compared to pre-intervention [50].
Another study indicated that 6 g/day GLN supplementation over 1
week caused a lower level of CK in the GLN supplementation group
in the recovery stage compared to the immediately after exercise
(p <0.05) [73]. Six studies found no signicant relationship be-
tween GLN supplementation and blood CK after exercise
[52,62,65,74,78,79].
7.2. Quantitative synthesis
Data from 6 studies [16,44,62,69,72,77], including 56 treatments
and 56 controls, was used to explore the effects of GLN on blood
glucose immediately after exercise. Two studies tested two
different doses of GLN on blood glucose levels [62,77], therefore
each dose was entered in the analysis separately. Overall, 8 effect
sizes were entered to compare the relationship between GLN
supplementation and blood glucose post-exercise. There were no
differences between low and high doses of GLN in affecting blood
glucose [77]. According to these studies, GLN intake in athletes did
not correlate with blood glucose levels (mean difference ¼0.27
[95% CI: 0.24, 0.78] mmol/l; P ¼0.29; Fig. 5b). There was a high
heterogeneity between these studies (I
2
¼88.5%, p <0.001). Po-
tential sources of variation were evaluated by subgroup analysis,
and it was found that supplement doses of more than 0.2 gr/kg BW
and supplement form (glutamine or sustamine) could be sources of
heterogeneity (I
2
¼87.3%, p <0.001; and I
2
¼87.0%, p <0.001,
respectively). The study quality subgroup analysis did not provide
further information in detecting sources of heterogeneity. Sub-
group analysis showed that, supplementation by glutamine
dipeptide (sustamine) has more efciency in maintaining blood
glucose after exercise compared to supplementation by glutamine
(0.51 [95% CI: 0.18, 0.83] mmol/l; P ¼0.002 vs. 0.01 [95% CI: 0.60,
0.57] mmol/l; P ¼0.96). However, in high-quality studies, plasma
glucose levels were signicantly lower in the GLN group compared
to the placebo group (n ¼5, mean difference ¼0.46 [95%
CI: 0.55, 0.36] mmol/l; P <0.001). All studies included
A.R. Ahmadi et al. / Clinical Nutrition xxx (2018) 1e16 11
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YCLNU3454_proof 14 May 2018 11/16
Please cite this article in press as: Ahmadi AR, et al., The effect of glutamine supplementation on athletic performance, body composition, and
immune function: A systematic review and a meta-analysis of clinical trials, Clinical Nutrition (2018), https://doi.org/10.1016/j.clnu.2018.05.001
endurance and team sportsathletes. Sensitivity analysis did not
provide further information.
Studies on 66 subjects from 3 studies [50,52,73] (36 treatments
and 35 control) did not show a signicant effect of GLN on blood CK
after exercise (mean difference ¼20.29 [95% CI: 86.55, 45.97]
UI/l; P ¼0.54; Fig. 5c). One study indicated no effect of dose on
blood CK changes [62]. There was no signicant heterogeneity
between trials (I
2
¼0.0%, P ¼0.67). Sensitivity analysis did not
show any change in results.
A meta-analysis carried out on three studies [44,64,67],
including 30 treated participants and 30 controls, did not nd any
signicant effect of GLN on blood GH immediately post-exercise
(mean difference ¼0.17 [95% CI: 1.50, 1.85] ng/l; P ¼0.83;
Fig. 5d). Articles were statistically heterogeneous (I
2
¼64.2%,
p¼0.06). Subgroup analysis did not nd any source of
heterogeneity.
8. Discussion
In the present meta-analysis,
L
-glutamine supplementation was
not associated with a signicant change in the athletes' immune
function (leukocyte, lymphocyte and neutrophil counts), aerobic
capacity (Vo2max), body composition (fat mass and lean body
mass), and plasma levels of glucose, CK and GH after exercise.
However, GLN supplementation resulted in a signicant weight
reduction in athletes.
8.1. Immune function
Although moderate exercise stimulates many of the immune
system functions, high-intensity exercise may suppress various
immune parameters by reducing s-IgA secretion, neutrophil
numbers, T and NK cells function as well as change in phagocyte
activation [81]. Early studies found that heavy-load exercise can
lead to a decrease in athletes' immune function, and proposed that
GLN effects are likely to prevent this condition [82]. According to
the meta-analysis, GLN did not affect leukocyte, lymphocyte, and
neutrophil numbers. However, GLN supplementation in doses more
than 0.2 gr/kg BW signicantly reduced neutrophil numbers,
compared to a placebo. Further, compared with high-quality
studies, leukocyte counts were signicantly higher in low-quality
studies. At the other extreme, some studies reported a signicant
alteration in immune function following GLN ingestion. The
following effects were variously reported with GLN supplementa-
tion as compared to a placebo: a decline in the incidence of infec-
tion in athletes [18]; changes in the ratio of CD4þ/CD8þ[41,54];
increase in the percentage of T-cells [14]; elevation in natural killer
activity [54]; increase in nasal Ig-A [47]; enhancement of leukocyte
numbers [51,52]; change in neutrophil counts [44,50,52]; increase
in IL-6 [46]; elevation in I
k
B
a
[53,55]; increase in HSP70 expression
[53,55]; and lower plasma levels of TNF-
a
[55]. It is likely that long-
term stress due to overtraining leads to a reduction in GLN syn-
thesis and at the same time increases the body's GLN demands [54].
It has been shown that the immune system needs GLN as an energy
source, and that it is also needed for construction of nucleic acid.
Additionally, lymphocytes and macrophages require this amino
acid for the proliferation and differentiation [83]. Moreover, GLN
supplementation can ameliorate stress-induced intestinal perme-
ability, which causes an increase in pro-inammatory plasma
proteins (i.e., TNF-
a
, IL-6, IL-7), activation of the NF-
k
B pathways,
and endotoxin leakage. In these ways, GLN can play a protective role
in the stabilization of the intestinal wall [55]. Nevertheless, most of
the studies failed to demonstrate any signicant effect of GLN
intake on the values of CD4þand CD8þ[14,42,43,48], NK cells
activity [14,43,84], B cell counts [14], s-IgA [1,47,84], plasma levels
of Ig A, M and G [50,52,54], leukocyte numbers
[14,16,41,43,45,48e50], lymphocyte counts [14,16,41e45,48,49],
neutrophil numbers [16,42,43,45,48,49], monocyte numbers
[43,48,49], plasma concentration of complements [14,50,52], CRP
[14], neopterine [14], IL-6 [14],IFɣ[14], ConA stimulated prolifer-
ative response [43], LAK [42e44], PHA proliferative response
[42,43], and phagocyte activity [50,52]. Based on these ndings, it is
Fig. 5. Forest plot detailing weighted mean difference and 95% condence in-
tervals for the impact of GLN supplementation on aerobic capacity and blood
markers.A,Vo
2
max; B, Serum glucose post-exercise; C, creatine kinase; D; growth
hormone. Square size shows the weight of study in pooled analysis and horizontal bars
reecting the 95% condence interval.
A.R. Ahmadi et al. / Clinical Nutrition xxx (2018) 1e1612
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immune function: A systematic review and a meta-analysis of clinical trials, Clinical Nutrition (2018), https://doi.org/10.1016/j.clnu.2018.05.001
more likely that GLN does not affect immunosuppression, as has
been remarked by athletes. Although the study duration and sup-
plement dose are important factors to cause the desired effect, this
meta-analysis found that there was no difference in acute or
chronic intervention duration. However, in some studies, changes
in immune function varied over different times [14,50]. Also, the
supplement dosage made some difference, as described earlier, in
terms of neutrophil numbers.
8.2. Body composition
According to our research, GLN supplementation has no signif-
icant relationship with lean body mass and fat mass, but there was
an inverse correlation with body weight. Consistent with the meta-
analysis, several studies found no correlation between consuming
GLN and body composition [52,57,59]. However, some studies have
shown contrary results. Hakimi [67] and Ghanbarzadeh [63]
showed that GLN supplementation increases body weight and
lean mass, and signicantly reduces fat mass. Lehmkuhl and col-
leagues [3] suggested that both body mass and LBM increased,
while fat mass did not show any signicant change after an 8-
weeks GLN supplementation. One reason for this variation could
be the differences in the amount of GLN intake. As Lehmkuhl [3]
showed, adding 4 g of GLN to creatine monohydrate did not
change body weight and LBM signicantly, compared to creatine
monohydrate alone, though that this may have been due to an
inadequate dose of GLN. For GLN to have a signicant effect on
increasing muscle GLN synthetase [63] and on subsequent in-
creases in muscle protein synthesis and muscle mass maintenance
[7], the amount of GLN must be high enough to increase plasma
GLN levels [85].
The results collected in this paper demonstrate an inverse as-
sociation between the intake of GLN supplements and body weight.
This relationship disappeared following eliminating one of the
studies [63]. This weight loss may either be caused by the intensity
of the training program [63] or the effect of GLN on reducing body
fat. GLN can mediate lipid metabolism and thereby have an impact
on the amount of fat tissue [63]. Weight loss may also be due to the
effect of exercise on body uid balance [52]. Another reason for the
differences in study results on the effects of GLN on body compo-
sition could be due to the differences in the mixture of supplements
[63]. Considering the duration of the studies, all studies that
included in the meta-analysis were chronic intervention.
8.3. Athletic performance
This meta-analysis concluded that GLN supplementation has no
effect on the aerobic performance of athletes. Also, there was no
effect of GLN on oxygen consumption, oxygen kinetics in muscles,
energy cost and aerobic capacity [10,58,60,68,71]. Furthermore,
GLN showed no effect on heart rate and thus does not affect
muscular blood supply [47,58,66]. In contrast to these ndings,
some researchers have found a signicant relationship between
GLN supplementation and a faster mean Vo2 response time, and
increases in muscle oxygen consumption, muscle deoxygenation
kinetics, oxidative metabolism, and aerobic power [60,63]. It might
be that GLN helps to preserve phosphocreatine and glycogen in
muscle oxidative bers as a tricarboxylic acid cycle intermediate
metabolite [63]. Overall, though, it appears that GLN plays a minor
role in improving athletic aerobic ability.
Studies about the effects of GLN on anaerobic performance
present more conicting evidence. Several studies reported a sig-
nicant improvement in anaerobic power [6,63,70], strength
[65,76], perceived exertion [16,68], reaction time and shooting
performance [66,80]. At the other extreme, some studies failed to
nd a signicant relationship between GLN ingestion and anaer-
obic performance, muscle strength, exibility, lactate threshold,
motor response, vertical jump and lower body reaction [10,66,71].
In general, it seems that GLN has a positive effect on some aspects
of anaerobic power and strength. Additionally, based on previous
studies, it may be effective in enhancing athletes' tolerance and
exercise duration prior to fatigue [6,61]. Furthermore, GLN helped
to diminish muscle soreness more quickly [65,76]. However, in
some trials, GLN did not affect athletic endurance [56,70,71,74], nor
the time nor intensity of muscle soreness [65,74], and in some
cases, unfavorable consequences were even observed [68]. GLN has
several effects on the immune system and maintaining the body's
protein balance, as well as perhaps playing an important role in
cellular regulatory systems [86]. GLN possibly also improves muscle
function by alleviating inammatory responses due to exercise
[87]. Also, the reduction in protein degradation caused by GLN leads
to an increase in the size of fast twitch bers and enhances buff-
ering capacity [88]. In addition, it is suggested that GLN improves
muscle strength and anaerobic power through a number of other
functions, such as: increasing muscle cell hydration, which reduces
the release of CK, inammatory processes, and cell lesions [89,90];
reducing sensitivity to dehydration by contributing to a more ef-
cient uid and electrolyte uptake [66]; promoting muscle glycogen
re-synthesis during the recovery period [38]; and reducing plasma
lactate concentration [68]. The discrepancies that have been
observed in different studies may be due to the form and dosage of
supplements, the study duration and quality, the difference in the
type and intensity of exercise, and the gender of the participants.
For example, some GLN derivatives, such as sustamine, are more
stable than GLN itself [91]. Furthermore, combining GLN with
maltodextrin has been shown to be more effective than adminis-
tering the two separately [70]. Also, contrasting results were ob-
tained in one study comparing the effects of GLN on strength
between male and female participants [76].
8.4. Blood markers (CK, GH, glucose)
The results of the current meta-analysis indicated that GLN
supplementation did not signicantly affect blood glucose, growth
hormone, and creatine kinase levels.
Since there was signicant heterogeneity between studies
related to blood glucose and growth hormone, the results did not
reect factual ndings, while the studies of creatine kinase did not
have any heterogeneity. The heterogeneity between studies related
to glucose was not abolished by performing subgroup analysis, but
the supplement dosage and form were identied as sources of
heterogeneity. In line with the meta-analysis, most of the studies
did not nd a signicant correlation between the consumption of
GLN and blood glucose [16,44,62,69,72,77]. Among these studies,
one study showed higher levels of blood glucose in the placebo
group compared to the supplementation group [72] ethis may be
due to the administration of maltodextrin to the placebo group,
while the intervention group was given only GLN. Thus, it is
possible to conclude that differences in the type of placebo and
intervention duration can lead to different results. Further, this
meta-analysis also showed that supplementation by sustamine, but
not glutamine, may help athletes in maintaining blood glucose
post-exercise. This can be the result of enhancing muscle glutamine
uptake by supplementation in dipeptide form [92] that can increase
glucose availability. In addition, another amino acid that presents in
this dipeptide, alanine, is a gluconeogenic amino acid and may have
a contribution to increasing blood glucose levels [93]. Another
potential factor that can affect the results from glucose levels, is
sport type. All studies that investigated the effect of glutamine on
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Please cite this article in press as: Ahmadi AR, et al., The effect of glutamine supplementation on athletic performance, body composition, and
immune function: A systematic review and a meta-analysis of clinical trials, Clinical Nutrition (2018), https://doi.org/10.1016/j.clnu.2018.05.001
blood glucose after exercise recruited endurance and team sport
athletes.
Among the studies in relation to GH, one study showed
increased levels of this hormone in response to GLN [67]. Other
studies also indicated that GLN can increase resting levels of GH
[94,95], but not post-exercise levels [95]. Also, the stimulatory role
of GLN in growth hormone release can be seen during prolonged
critical illness when GLN levels drop below the normal range [96].
The type of exercise also affects the growth hormone response to
GLN. Some studies have shown that GLN supplementation during
prolonged heavy endurance training has no effect on increasing
serum GH [64].
Creatine kinase is a marker of muscle damage that increases in
the blood after exercise and is closely linked to energy metabolism
[73]. Consistent with other studies [50,52,65,74], the meta-analysis
found no effect of GLN supplementation on blood levels of CK, but
Koo et al. [73] have shown that GLN reduces CK levels. The reduced
levels of serum CK after GLN supplementation may be due to the
cellular hydration state. The transportation of GLN into the cell is
sodium-dependent. The subsequent entry of water intothe cell and
release of potassium from the cells [90,97] inuences the cellular
volume and hydration status, which causes cellular resistance
against lesions, and decreases the release of intracellular enzymes
such as CK [89,90].
9. Conclusion
This systematic review and meta-analysis suggested that GLN
supplementation has no effect on leukocyte, lymphocyte and
neutrophil counts. Although some studies reported that GLN
signicantly affects immune function, most studies found no as-
sociation between GLN ingestion and immunosuppression.
Considering the effect of GLN supplementation on athletic perfor-
mance, it appears that GLN does not affect aerobic performance, but
regarding anaerobic performance and strength it could not be
determined decisively because of the limited number of studies.
Additionally, GLN may have some effects in diminishing muscle
soreness more quickly, but it should be conrmed by meta-analysis
and needs more studies. In relation to body composition, this study
showed that GLN resulted in greater weight reduction, but that the
ratio of fat mass and lean body mass did not change. Regarding the
post-exercise blood markers, this study found that supplementa-
tion in the form of dipeptide, but not glutamine alone, may result in
an improvement in blood glucose post exercise. However, because
of the low number of studies, this cannot be concluded rmly.
There were some limitations in present study including lack of
adequate studies to perform the meta-analysis in all areas regards
to athletic performance (anaerobic performance, strength, exi-
bility, etc.), studies in non-English languages that was not possible
to be extracted, inadequate information provided by some studies.
Moreover, in the meta-analysis, it is not possible to analyze the
various measurement parameters for a feature together and this
can cause more limitations in interpreting the results. There is a
need for more randomized clinical trials to determine whether GLN
has a signicant effect on athletic performance, immune function,
and body composition, or not. Moreover, the present study suggests
that the efcacy of GLN supplementation could be affected by the
study duration, quality, and supplement dose and type.
Compliance with ethical standards
Ramezani Ahmadi A, Rayyani E, Bahreini M, and Mansoori A
declare that they have no conict of interest. For this type of study
formal consent is not required. This article does not contain any
studies with human participants or animals performed by any of
the authors.
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Please cite this article in press as: Ahmadi AR, et al., The effect of glutamine supplementation on athletic performance, body composition, and
immune function: A systematic review and a meta-analysis of clinical trials, Clinical Nutrition (2018), https://doi.org/10.1016/j.clnu.2018.05.001
... While the results of research [18][19][20][21] indicate an increase in the number of leukocytes after taking glutamine supplementation. The difference in the results is due to the type of training and duration of activity, gender and level of readiness of the subjects. ...
... The discrepancy appears to be due to differences in the duration of supplementation. Ahmadi [19] reported that Bruce test could not make a significant difference in the number of monocytes. The reason for the difference with the obtained result is the difference in the level of readiness of the subjects. ...
Article
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Athletes with heavy training loads are prone to infectious diseases. It has been shown that these exercises may suppress immune function. The aim of this study was to investigate the effect of one session of intense physical activity with glutamine supplementation on selected factors of wrestlers' immune system. For this purpose, 20 wrestlers were selected and randomly divided into two groups of supplement and placebo. The first blood sample was taken from the subjects. Then they did the Bruce test. Immediately after the end of the test, blood samples were taken from the subjects for the second time and then to the supplement group. The glutamine supplement was given the same amount of maltodextrin per kilogram of body weight and the placebo group. Blood samples were taken from the subjects for the third and fourth time 1 and 2.5 hours after taking the supplement or placebo. After measuring blood factors, the findings were statistically analyzed (ANOVA) at a significance level of p <0.05. The results showed that the percentage of neutrophils in the supplement group increased significantly 2.5 hours after supplementation compared to immediately after exercise and 1 hour after supplementation. This increase was less in the supplement group than in the placebo group. The percentage of lymphocytes in the supplement group decreased significantly 2.5 hours after supplementation compared to the pre-test, immediately after exercise and 1 hour after supplementation, which was less in the supplement group than the placebo group. The percentage of monocytes in the supplement group increased significantly 2.5 hours after supplementation compared to immediately after exercise. This increase was less in the supplement group than in the placebo group. The results of this study showed that glutamine supplementation during strenuous exercise has beneficial effects on the immune system of athletes.
... Therefore, it is involved in various essential functions. Despite this, it did not show ergogenic abilities; on the other hand, it is adequate to counteract a decrease in the immune system's effectiveness due to endurance and/or intense activities and recovery from injury; both situations are frequent in CS [72,73]. ...
Article
Full-text available
In recent years, nutrition applied to the sport has had a great response from technicians and science, justifying more and more the use of the support of food supplements, especially when considering elite athletes and/or professionals. The term combat sport refers to a varied and heterogeneous group of sporting activities, some recognized by the International Olympic Committee, others not; many aspects unite them. They are considered “minor” sports if compared to football, basketball, baseball, as they are less popular at a professional level, but with a great deal of participation at the amateur level; in this sense, everything concerning nutrition and food supplementation is often delegated to the practitioners themselves. This work would like to resume the current (however not abundant) literature and suggest a correct integration, based on the literature available even if not sport-specific, providing a tool for technicians and a starting point for specific works in the future.
... GABA is also important for human health for its potential anti-hypertensive effect. Glutamine had a weight loss effect (Ahmadi et al., 2019), GABA had a blood pressure lowering effect (Inoue et al., 2003) and fatigue reducing effect (Kanehira et al., 2011), arginine and citrulline had a blood pressure lowering effect in humans (Khalaf et al., 2019), histidine has been shown to improve insulin resistance (Feng et al., 2013), and tyrosine has been suggested to enhance cognitive function in humans (Colzato et al., 2013). Thus, free amino acids have a variety of health-promoting effects, and since these functional amino acids were increased by mycorrhizal symbiosis, so, mycorrhizal symbiosis is expected to enhance such functions. ...
... It encompasses about 60% of free AA in skeletal cells [3,4] and 20% in plasma [5]. Furthermore, L-Gln has a wide range of cellular and physiological functions including protein synthesis [6], lipid metabolism, and cell growth [7,8], all of which are associated with muscle growth and proliferation [9]. By inducing lymphocyte proliferation, Gln is considered as booster of immune system. ...
Article
Full-text available
Objective: Two follow-up studies (experiments 1 and 2) were conducted to determine the effects of L-glutamine supplementation on degradation and rumen fermentation characteristics in vitro. Methods: First, rumen liquor from three cannulated cows was used to test L-Gln (50 mM) degradation rate and ammonia-N production at 6, 12, 24, 36, and 48 h after incubation (exp. 1). Second, rumen liquor from two cannulated steers was used to assess the effects of five levels of L-Gln including 0 (control), 0.5, 1, 2, and 3% at 0, 3, 6, 12, 24, 36, and 48 h after incubation on fermentation characteristics, gas production, and degradability of nutrients (exp. 2). Results: In exp. 1, L-Gln degradation rate and ammonia-N concentrations increased over time (p<0.001). In exp. 2, pH was reduced significantly as incubation time elapsed (p<0.001). Total gas production tended to increase in all groups as incubation time increased. Acetate and propionate tended to increase by increasing Gln levels, whereas levels of total volatile fatty acids (VFAs) were the highest in 0.5% and 3% Gln groups (p<0.001). The branched-chain VFA showed both linear and quadratic effects showing the lowest values in the 1% Gln group particularly after 6 h incubation (p<0.001). L-Gln increased CP degradability (p<0.001), showing the highest degradability in the 0.5% Gln group regardless of incubation time (p<0.05). Degradability of acid detergent fiber and neutral detergent fiber showed a similar pattern showing the highest values in 0.5% Gln group (p<0.10). Conclusion: Although L-Gln showed no toxicity when it was supplemented at high dosages (2~3% of DM), 0.5% L-Gln demonstrated the positive effects on main factors including VFAs production in-vitro. The results of this study need to be verified in further in-vivo study.
... Either glutamine (6 g/day) or placebo was administered orally for 20 consecutive days. The dose and time for glutamine supplementation were selected according to the information provided in references [12,[20][21][22]. Seven days before the beginning of the study, a blood sample was obtained (baseline). ...
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Full-text available
Scientific evidence supports the role of L-glutamine in improving immune function. This could suggest a possible role of L-glutamine in recovery after intense exercise. To this end, the present report aimed to study if oral L-glutamine supplementation could attenuate muscle damage in a group of players of a mainly eccentric sport discipline such as basketball. Participants (n = 12) were supplemented with 6 g/day of glutamine (G group) or placebo (P group) for 40 days in a crossover study design (20 days with glutamine + 20 days with placebo and vice versa). Blood samples were obtained at the beginning and at the end of each period and markers from exercise-induced muscle damage were determined. The glutamine supplemented group displayed significantly low values of aspartate transaminase, creatine kinase and myoglobin in blood, suggesting less muscle damage compared to the placebo. In addition, adrenocorticotropic hormone levels were lower in the glutamine supplemented group than in the placebo. As a result, the circulating cortisol levels did not increase at the end of the study in the glutamine supplemented group. Altogether, the results indicate that glutamine could help attenuate exercise-induced muscle damage in sport disciplines with predominantly eccentric actions.
... In the realm of sports science, majority of studies focused on the change of exercise performance and anthropometric change following the oral supplementation of glutamine and arginine [58,59]. Therefore, as a benefit in return, how the exercise types, intensities, or duration determine the waxing and waning of metabolic profiles needs to be verified as Oov Pilates program in our study led to the change of specific metabolites associated with short-term and moderate exercise intensity. ...
Article
Full-text available
Pilates has been known as exercise intervention that improves the function of pelvic floor muscle (PFM) associated with impacting urinary incontinence (UI). This study investigated the effect of Pilates on UI in Korean women by determining the change in functional movement of PFM (FMP) and metabolic profiles. UI group with Pilates (UIP, n = 1