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Advanced physiological roles of
guanidinoacetic acid

Sergej M. Ostojic

European Journal of Nutrition

ISSN 1436-6207
Volume 54
Number 8

Eur J Nutr (2015) 54:1211-1215

DOI 10.1007/s00394-015-1050-7

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 Author's personal copy
Eur J Nutr (2015) 54:1211–1215
DOI 10.1007/s00394-015-1050-7
REVIEW
Advanced physiological roles of guanidinoacetic acid
Sergej M. Ostojic1,2 
Received: 30 July 2015 / Accepted: 16 September 2015 / Published online: 28 September 2015
© Springer-Verlag Berlin Heidelberg 2015
Abstract  Dietary guanidinoacetic acid (GAA) seems to
improve cellular bioenergetics by stimulating creatine bio-
synthesis. However, GAA could have other biological func-
tions that might affect its possible use as a food ingredient
in human nutrition. In this paper, we identified several alter-
native physiological roles of supplemental GAA, including
the stimulation of hormonal release and neuromodulation,
an alteration of metabolic utilization of arginine, and an
adjustment of oxidant–antioxidant status. A better knowl-
edge of how GAA affects human physiology may facilitate
its use as an experimental nutritional intervention for novel
purposes and conditions.
Keywords  Guanidinoacetic acid · Creatine · Insulin ·
Arginine · Pro-oxidant
Introduction
Guanidinoacetic acid (GAA; chemical formula C3H7N3O2)
is a naturally occurring amino acid derivative that acts as
a direct precursor of creatine, an essential compound in
the energy metabolism of muscle and nerve tissue. GAA
has been identified as a component of human metabolism
approximately 80 years ago [1], with fundamental meta-
bolic pathways of GAA biotransformation well described
[2, 3] (Fig. 1).
* Sergej M. Ostojic
sergej.ostojic@chess.edu.rs
1
Biomedical Sciences Department, Faculty of Sport
and Physical Education, University of Novi Sad, Lovcenska
16, 21000 Novi Sad, Serbia
2
University of Belgrade School of Medicine, Belgrade, Serbia
In the past decade or so, GAA has redrawn attention as
an experimental dietary additive in human nutrition. Die-
tary GAA improved clinical outcomes and prevented mus-
cle mass loss in patients with chronic renal failure [4]. Sup-
plemental GAA also enhanced muscular performance in
healthy volunteers [5] and improved health-related quality
of life in patients with chronic fatigue syndrome [6]. Above
trials suggested that GAA could stimulate cellular bioen-
ergetics through enhanced creatine biosynthesis, with con-
firmed amplified creatine availability in the skeletal muscle
after GAA ingestion in young pigs [7] and humans (Ostojic
et al. unpublished data). However, GAA could have other
physiological roles in the human body that might be rel-
evant for its possible use as a novel dietary supplement in
human nutrition. In this paper, we will advance new pos-
sibilities for GAA actions in vivo.
Alternative mechanisms for GAA action
Historical clinical studies from the 1950s were the first
to report a significant capacity of dietary GAA to affect
human physiology. Dispensed as a creatine precursor, die-
tary GAA improved work tolerance and functional abilities
in patients with cardiac decompensation and acute anterior
poliomyelitis [8, 9]. Interestingly, authors suggested that
GAA might have additional physiological effects besides
creatine biosynthesis, yet no other mechanisms of action
have been evaluated or proposed. Our group recently nomi-
nated a number of mechanisms that might be related with
performance-enhancing capacity of dietary GAA [5], with
the net effect of GAA yet to be revealed. Now, we identi-
fied several alternative physiological roles of supplemental
GAA, including possible stimulation of hormonal release
and neuromodulation, alteration of metabolic utilization
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1212
Fig. 1  Guanidinoacetic acid (GAA) biotransformation. GAA is
synthesized from non-essential amino acids glycine and l-arginine,
with this reaction catalyzed by the enzyme l-arginine–glycine ami-
dinotransferase (AGAT; EC number 2.1.4.1). AGAT is located mainly
in the kidneys and pancreas. The uptake of GAA through the diet is
considered negligible (e.g., meat GAA content >10 mg/kg); however,
no reliable data tables for GAA content in various foods are avail-
able. After being transported to the liver (also pancreas, reproductive
organs), GAA is methylated to yield creatine. This reaction is cata-
lyzed by the enzyme guanidinoacetate N-methyltransferase (GAMT;
EC number 2.1.1.2) and requires transfer of a methyl group from
S-adenosylmethionine (SAM) to GAA, to form creatine and S-adeno-
sylhomocysteine (SAH). Black boxes indicate enzymes AGAT (1) and
GAMT (2)
of arginine, and oxidant–antioxidant status adjustment
(Fig. 2).
Previous studies suggested that exogenous GAA stimu-
lates insulin secretion in rodents, with GAA causing an
Fig. 2  Advanced physiological
roles of guanidinoacetic acid.
Abbr. GABA—γ-aminobutyric
acid
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Eur J Nutr (2015) 54:1211–1215
immediate increase in plasma insulin (up to 150 µU/ml)
that persisted for approximately 20 min [10]. This GAA-
driven insulin release appears to be more potent as com-
pared to creatine or arginine [11, 12], with the presence of
positive charge on the side chain of the compound possi-
bly responsible for a difference in response [13]. Although
highly speculative, this polarity of GAA molecule might
affect membrane depolarization in pancreatic islets cells
that stimulates insulin secretion through protein kinase A-
and C-sensitive mechanisms. In addition, exogenous GAA
decreases plasma glucose [14], with improved insulin
sensitivity seen as another insulin-related mechanism of
GAA action. This effect might be also due to GAA poten-
tiation of protein kinases that modulate the insulin recep-
tor activity on target cells. Having all this in mind, dietary
GAA might be approached as an insulinotropic compound
that affects insulin homeostasis and ameliorates hypergly-
cemia, with GAA possibly used as an anti-diabetic and/or
anabolic agent. However, no human study so far evaluated
possible clinical potential of GAA-induced insulin stimu-
lation neither its underlying mechanisms. Furthermore, it
seems that GAA can act as a moderate glucagon secreta-
gogue [12], yet the net effect of GAA intake on hormones
regulating glucose metabolism is currently unknown.
Second, dietary GAA can be used as an efficacious
replacement for arginine in animal nutrition [15]; the
arginine-sparing effect of GAA might facilitate the use of
more arginine for other physiological functions, includ-
ing protein anabolism, cellular signaling, and hormonal
release. Recent studies [16–18] reported that supplemental
GAA could increase growth performance and weight gain
in broilers, suggesting more arginine is available for pro-
tein synthesis and breast meat yield. So far, no human stud-
ies evaluated arginine sparing or its utilization for protein
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Eur J Nutr (2015) 54:1211–1215 1213
synthesis during GAA supplementation. Furthermore, since
more arginine could drive growth hormone (GH) produc-
tion and nitric oxide (NO) synthesis [19], dietary GAA
might additionally affect growth and NO-mediated func-
tions by making extra arginine theoretically available for
above functions after GAA intervention. This hypothesis
has not been tested in vivo so far.
Third, GAA acts as a possible activator of gamma-
amino butyric acid (GABA) receptors in the brain and
peripheral tissues [20]. Since GABA is the chief inhibi-
tory neurotransmitter in the nervous system, exogenous
GAA might act as a neuromodulator and affect neuronal
excitability, muscular tone, and/or brain development. Neu
and co-workers [21] reported the interaction of GAA with
neuronal GABAA receptors as a candidate mechanism
explaining neurological dysfunction in guanidinoacetate
methyltransferase (GAMT) deficiency, an autosomal reces-
sively inherited disorder of creatine biosynthesis. Due to
its structural similarity with GABA, GAA activates neu-
ronal voltage-gated or ligand-gated chloride channels and
impairs spontaneous activity of neurons. This probably
happens when GAA accumulates in high concentrations in
the brain and plasma (~10–30 μM) in GAMT deficiency.
However, whether dietary GAA acts as GABAA agonist
and affects neuromodulation in physiological conditions is
currently unknown. Our group recently reported that GAA
loading (3 g/day) decreases plasma GABA levels after
3 weeks of intervention in healthy men [22], suggesting
possible GABAergic action of dietary GAA although the
exact mechanism of GAA action remained undisclosed. No
effects of dietary GAA were evaluated regarding GABA-
mediated neuronal or muscular excitability of the interven-
tion. The theory of GABA-mediated mechanism of dietary
GAA action requires further investigation.
Fourth, GAA might behave as a direct substrate for cre-
atine kinase (CK) and compensatory phosphagen [23], with
phosphorylated GAA serving as a phosphocreatine mimetic
and an alternative energy donor, at least when the availabil-
ity of creatine is reduced. During normal conditions, when
availability of creatine is normal, the potential of GAA to
act as a substrate for CK is probably negligible. GAA com-
petes with creatine, with the flux through the CK reaction
~100 times lower for GAA as compared to creatine [24].
However, in creatine-deficient conditions, GAA might
completely saturate CK and act as a substitutional phos-
phagen. This is confirmed in GAMT-knockout mice, where
resting metabolite level of phospho-GAA (not normally
present) did not differ from the phosphocreatine peak in
wild-type mice [25], implying a notable utilization of GAA
by CK. Creatine-deficient mice are able to cope with ener-
getically compromised conditions by using phospho-GAA
[26, 27]. This suggests that GAA might act as a possible
proxy for creatine in creatine deficiency, yet its ability for
replenishment of cellular energy seems inferior as com-
pared to creatine. Anyhow, no data are currently available
to evaluate possible capacity of dietary GAA as an alterna-
tive energy donor in human physiology or pathophysiology.
Fifth, previous animal studies reported that exogenous
GAA might affect oxidant–antioxidant system, acting
either as a pro-oxidant or an antioxidant compound. GAA
induces oxidative stress after experimental intrastriatal
infusion [28], or excessive accumulation in pathological
conditions [29], while dietary GAA improves antioxida-
tive status by elevating total antioxidant capacity and the
activities of several antioxidant enzymes [30]. Contrasting
results of the previous studies are accompanied with dif-
ferent levels of GAA achieved after GAA administration/
accumulation. Pro-oxidant effects are noticed after intrac-
erebral accumulation and highly elevated brain GAA con-
centrations (~100 µmol/L), while antioxidant effects seem
to appear after GAA ingestion and relatively low post-
administration serum levels of GAA (~5 µmol/L). Chemi-
cally, GAA yields reactive oxygen species since it donates
an electron from its conjugate base and generates superox-
ide, a strong free radical [31]. Therefore, pure GAA serves
as a direct pro-oxidant. On the other hand, GAA-related
metabolites (creatine and arginine) might be able to quench
free radicals after GAA ingestion [30], suggesting indi-
rect antioxidant effect of GAA utilization. Theoretically,
if GAA metabolism remains undisturbed and/or low-to-
modest quantities of exogenous GAA have been provided,
a cumulative effect of the intervention might be neutral
or antioxidant protection through creatine- and arginine-
driven medium. Nevertheless, as long as GAA metabolism
is irregular or the compound accumulates in high amounts,
GAA behaves as a strong pro-oxidant and can induce oxi-
dative stress. However, an explicit exposure–response rela-
tionship concerning oxidant–antioxidant status of dietary
GAA remains unknown.
Finally, GAA might act as a moderate vasodilation agent
that increases the blood flow due to a decrease in vascu-
lar resistance. Researchers from the University of Kansas
School of Medicine were the first to report a vasodilation
and lowering of blood pressure in clinical patients medi-
cated with GAA, when the compound was administered
intravenously (1 % GAA solution) or orally (1–20 mg/kg)
[32–34]. Likewise, coronary blood flow increased with a
small dose of GAA in dogs, while higher doses induced
a more sustained drop in blood pressure [35]. While cre-
atine has no characteristic effect upon the blood pressure,
GAA was described as a powerful depressor substance.
This effect might be due to GAA-driven inhibited methyla-
tion of norepinephrine that affects its half-life and sympa-
thetic effects [36]. Chalier [37] suggested that GAA prob-
ably causes vascular dilation by an alternative mechanism.
Hypothetically, GAA may indirectly lead to vasodilation
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1214
through arginine sparing and arginine-mediated NO pro-
duction, with NO acting as an endothelium-derived relax-
ing factor [38]. However, no recent human studies evalu-
ated possible anti-hypertensive effects of GAA or its
direct or indirect mechanisms of action in the clinical
environment.
Challenges and barriers in GAA research
Before one substantiates each of the possible alternative
functions of GAA in the human body, several issues con-
cerning GAA research need to be addressed as well. GAA
is usually recognized as a pathophysiological substrate
of GAMT deficiency, and accumulated GAA in the brain
and serum accompanies pathophysiological outcomes of
this disorder [39]. A number of studies advancing GAA
roles originate from case reports in patients with GAMT
deficiency, or experimental models of GAMT deficiency,
where GAA was administered exogenously (typically by
intracerebral or intravenous injection) to mimic brain GAA
levels found in clinical patients. Those studies are charac-
terized by two general features: (a) GAA levels in body
fluids are 60–1000 times higher than in normal controls,
while creatine pool is depleted, and (b) neurological dys-
function is mainly attributed to the increase in GAA levels.
GAA seems to be an active key metabolite causing neuro-
logical effects in such research models, yet the lack of cre-
atine is highly neurotoxic by itself as evidenced by other
neurological disorders in which there is no accumulation
of GAA [40]. Having this in mind, the mechanism lead-
ing to neurological effects in such studies initially attrib-
uted to GAA could be a result of GAA abundance, lack
of creatine, or a combination of both. In addition, above
models are of modest practical significance since clinically
relevant high concentrations of GAA (5–10 µM in cer-
ebrospinal fluid) are highly unlikely to happen in normal
population where GAA concentration in human cerebrospi-
nal fluid and plasma is in the nanomolar range, which is
probably not sufficient to affect neuronal activity. Further-
more, GAA utilization and transport seems to be qualita-
tively and quantitatively different in GAMT deficiency as
compared to the physiological conditions [41]. Therefore,
one should carefully interpret the results of above trials
concerning advanced physiological roles of dietary GAA
in the human body. Instead, studies investigating behavior
of GAA after enteral administration might be more effec-
tive and practical in advancing physiological roles of this
compound and its possible use as a food additive in human
nutrition. However, those studies are rather scarce and frag-
mentary, usually lacking mechanistic approach, long-term
design, and large samples. They are also characterized by:
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Eur J Nutr (2015) 54:1211–1215
(a) insufficient knowledge on dietary GAA pharmacoki-
netics and pharmacodynamics, (b) underdeveloped dose–
response models for supplemental GAA, (c) limited infor-
mation about GAA interaction with other nutrients and/or
pharmacological agents, (d) poorly addressed safety issues
of GAA ingestion, (e) missing information on the effects
of dietary GAA in specific populations, and (f) unresolved
regulatory status of supplemental GAA in the USA and
Europe. In particular, more randomized controlled trials
are needed to quantify practical biomedical significance of
supplemental GAA as compared to analogous compounds
in both healthy population and clinical patients. A better
knowledge of how GAA affects human physiology may
facilitate its use as an experimental nutritional intervention
for novel purposes and conditions.
Conclusion
Besides serving as an immediate precursor for creatine, it
seems that GAA has other physiological roles that might
be relevant for its possible use as a food additive in human
nutrition. GAA might stimulate insulin secretion and insu-
lin sensitivity, spare dietary arginine and facilitate its use
in protein synthesis, hormonal release, and vasodilation,
modulate GABA utilization and function, serve as an alter-
native energy donor during creatine deficiency, and affect
oxidant–antioxidant balance. Characterization of advanced
roles of dietary GAA requires further studies.
Acknowledgments  Supported by the Serbian Ministry of Science
(Grant No. 175037).
Compliance with ethical standards 
Conflict of interest  There is no conflict of interest in this study.
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