Creatine supplementation and glycemic control: a systematic review

Abstract

The focus of this review is the effects of creatine supplementation with or without exercise on glucose metabolism. A comprehensive examination of the past 16 years of study within the field provided a distillation of key data. Both in animal and human studies, creatine supplementation together with exercise training demonstrated greater beneficial effects on glucose metabolism; creatine supplementation itself demonstrated positive results in only a few of the studies. In the animal studies, the effects of creatine supplementation on glucose metabolism were even more distinct, and caution is needed in extrapolating these data to different species, especially to humans. Regarding human studies, considering the samples characteristics, the findings cannot be extrapolated to patients who have poorer glycemic control, are older, are on a different pharmacological treatment (e.g., exogenous insulin therapy) or are physically inactive. Thus, creatine supplementation is a possible nutritional therapy adjuvant with hypoglycemic effects, particularly when used in conjunction with exercise.

Full text

1 3
DOI 10.1007/s00726-016-2277-1
Amino Acids
INVITED REVIEW
Creatine supplementation and glycemic control:
a systematic review
Camila Lemos Pinto1 · Patrícia Borges Botelho1 · Gustavo Duarte Pimentel1 ·
Patrícia Lopes Campos‑Ferraz2,3 · João Felipe Mota1
Received: 24 May 2016 / Accepted: 8 June 2016
© Springer-Verlag Wien 2016
Introduction
Type 2 diabetes mellitus (T2DM) is a metabolic chronic
disease that is major public health problem leading to
increased morbility, mortality, and poor quality-of-life (IDF
2013; DeFronzo et al. 2015). In 2013, 382 million people
worldwide were estimated to have diabetes, among whom
80 % live in low- and middle-income countries; following
this trend until 2035, it is expected that the prevalence will
rise to 592 million people (IDF 2013). T2DM is mainly
characterized by a state of insulin resistance in muscle and
the liver, which can progress to impaired insulin secretion,
and, ultimately, sustained hyperglycemia (DeFronzo et al.
2015).
In healthy individuals, insulin signaling starts with insu-
lin binding to the insulin receptor tyrosine kinase (IR),
which phosphorylates a family of insulin receptor sub-
strates (IRSs), namely IRS1 and IRS2. This leads to acti-
vation of phosphatidylinositol 3-kinase (PI3K), which
promotes glucose transporter (GLUT) translocation to the
plasma membrane, where it takes up glucose into the cell
(DeFronzo 2009). In contrast, when there is increased ser-
ine phosphorylation of IRS, tyrosine phosphorylation is
inhibited and/or IRS is degraded, leading to insulin resist-
ance (Hiratani et al. 2005; Bouzakri et al. 2006; Copps and
White 2012). To adapt to the insulin resistance, β-cells aug-
ment insulin secretion to maintain normal blood glucose
concentrations. However, as time goes by, β-cells start to
fail and blood glucose levels start to rise, resulting in the
onset of T2DM (DeFronzo 2009).
T2DM can be effectively managed with lifestyle modi-
fications, such as dietary interventions and physical activ-
ity, and the use of some medications (Knowler et al. 2002;
Ramachandran et al. 2006; Pan et al. 1997). Creatine sup-
plementation has been pointed out as a novel promising
Abstract The focus of this review is the effects of cre-
atine supplementation with or without exercise on glucose
metabolism. A comprehensive examination of the past
16 years of study within the field provided a distillation of
key data. Both in animal and human studies, creatine sup-
plementation together with exercise training demonstrated
greater beneficial effects on glucose metabolism; creatine
supplementation itself demonstrated positive results in only
a few of the studies. In the animal studies, the effects of
creatine supplementation on glucose metabolism were even
more distinct, and caution is needed in extrapolating these
data to different species, especially to humans. Regarding
human studies, considering the samples characteristics, the
findings cannot be extrapolated to patients who have poorer
glycemic control, are older, are on a different pharmacolog-
ical treatment (e.g., exogenous insulin therapy) or are phys-
ically inactive. Thus, creatine supplementation is a possi-
ble nutritional therapy adjuvant with hypoglycemic effects,
particularly when used in conjunction with exercise.
Keywords Creatine · Type 2 diabetes · Exercise · Insulin ·
Glucose
Handling Editor: J. D. Wade.
* João Felipe Mota
jfemota@gmail.com
1 Clinical and Sports Nutrition Research Laboratory, Nutrition
Faculty, Federal University of Goias, Goiania, GO, Brazil
2 School of Physical Education and Sport, School of Medicine,
University of Sao Paulo, Sao Paulo, SP, Brazil
3 Faculty of Applied Sciences, State University of Campinas,
Limeira, SP, Brazil

C. L. Pinto et al.
1 3
strategy to modulate glucose metabolism, potentially alle-
viating insulin resistance condition.
Creatine (α-methyl guanidine-acetic acid), a guanidine-
derived compound, is a natural amine found in the cells of
the human body in a free and phosphorylated form (phos-
phorylcreatine) (Gualano et al. 2010; Wallimann et al.
2011; Guzun et al. 2011). It is synthesized endogenously
by the liver, kidney, and pancreas (~1–2 g/day) from argi-
nine, glycine, and methionine, or it can be consumed in the
diet mainly from meats (~1–5 g/day) (Wyss and Kaddurah-
Daouk 2000) Approximately 95 % of the creatine content
is found in the skeletal muscle, and a small portion can
be found in the brain, testicles, and bones (Gualano et al.
2010; Wallimann et al. 2011; Harris 2011).
Professor Roger Harris et al. 1992 demonstrated that
creatine supplementation was able to augment muscle cre-
atine, and phosphorylcreatine content. Since then, supple-
mentation has been largely used by healthy individuals and
athletes to improve performance, enhance gains in strength,
and attenuate atrophy, muscle weakness, and metabolic
dysfunction, such as T2DM (Branch 2003; Gualano et al.
2010; Pinto et al. 2016).
In the 70s, Alsever et al. (1970) and Marco et al. (1976)
demonstrated that creatine can modestly increase insulin
secretion in vitro. In 2000, Ferrante et al. observed that cre-
atine ingestion improved hyperglycemia and delayed the
onset of diabetes in a transgenic mice mimicking Hunting-
ton’s disease. Furthermore, Op’t Eijnde et al. (2001) dem-
onstrated that creatine supplementation was able to attenu-
ate the decline of muscle GLUT4 expression after 2 weeks
of immobilization in healthy individuals. Improvements
in glycemia were also showed in sedentary and T2DM
patients following creatine supplementation along with an
exercise training program (Gualano et al. 2011). The aim
of this systematic review was to compile the experimental
and clinical evidence regarding the effects of creatine sup-
plementation in glucose metabolism, covering a commonly
overlooked effect of creatine in literature, that could be
potentially relevant to clinicians, dietitians, and scientists
interested in T2DM.
We used the PRISMA (Preferred Reporting Items for
Systematic Reviews and Meta-Analyses) method to sys-
tematically review the articles that assessed the effects of
creatine supplementation with or without exercise training
on glucose metabolism. This systematic review was regis-
tered in PROSPERO with the number CRD42015016578.
We searched PubMed and Scopus for articles published
from 2000 up to June 2015 to identify all single- and dou-
ble-blind-controlled clinical trials and animal studies that
investigated the effects of creatine supplementation with or
without exercise training on glucose metabolism.
As shown in Table 1, the search terms used for creatine
supplementation and glucose metabolism were linked using
“OR” as a Boolean function, and the results of the two
searches were combined by utilizing the “AND” Boolean.
The search results from different databases were com-
bined and any duplicates were removed. Article titles and
abstracts were screened to exclude irrelevant studies. After
screening, papers were excluded based on the inclusion and
exclusion criteria. Finally, we manually searched the refer-
ences of the selected papers.
Inclusion criteria were as follows: (a) double- and sin-
gle-blind-controlled clinical trials investigating the effect of
creatine supplementation with or without exercise training
on any parameters related to glucose metabolism in healthy
individuals and diabetic patients; and (b) controlled animal
studies investigating the effect of creatine supplementation
with or without exercise training on any parameters related
to glucose metabolism in healthy and experimentally
induced diabetic animals.
Exclusion criteria were as follows: (a) non-controlled
or non-prospective-controlled studies (case studies, cross-
sectional studies, case–control, cohort or any other type of
other retrospective studies), study protocols, pilot studies,
letters-to-the editors, editorials, literature reviews, system-
atic reviews, screening or diagnostic studies, and qualita-
tive research; (b) in vitro studies; (c) studies with animal
samples other than rats or mice; (d) studies involving veg-
etarian; and e) studies in languages other than English and
Portuguese.
Figure 1 shows a flow chart of the literature selection.
Our database search yielded 170 records, of which 74 were
duplicates. Following the analysis of titles and abstracts, we
selected 96 studies for examination, 70 of which were not
relevant and related to the objective. After reading the full
text of 26 articles to screen for inclusion and exclusion cri-
teria, 12 articles were selected. From these selected articles,
we manually searched the references, and included seven
more articles in the analysis. The final sample consisted
of 19 articles included for analysis; 11 articles involved
animals, and 8 involved humans. Information on the ani-
mal and human studies is summarized in Tables 2 and 3,
respectively.
Animal studies
The results of the animal studies are shown in Table 2. A
total of 11 studies, including approximately 382 animals,
evaluated the effects of creatine supplementation with or
without exercise training on glucose metabolism. One
study did not mention the sample size (Eijnde et al. 2001).
Six studies were controlled (Ferrante et al. 2000; Eijnde
et al. 2001; Ju et al. 2005; Souza et al. 2006; Op’t Eijnde
et al. 2006; Araújo et al. 2013), and 5 were randomized and
controlled (Young and Young 2002; Rooney et al. 2002;

Creatine supplementation and glycemic control: a systematic review
1 3
Freire et al. 2008; Vaisy et al. 2011; Nicastro et al. 2012).
The median sample size was 63 animals (ranging from 8
to 72). Only Ferrante et al. (2000) studied mice; the other
studies used rats (Rooney et al. 2002; Young and Young
2002; Ju et al. 2005; Souza et al. 2006; Op’t Eijnde et al.
2006; Freire et al. 2008; Vaisy et al. 2011; Eijnde et al.
2001; Nicastro et al. 2012; Araújo et al. 2013). Eight stud-
ies investigated healthy animals (Young and Young 2002;
Rooney et al. 2002; Ju et al. 2005; Souza et al. 2006; Freire
et al. 2008; Eijnde et al. 2001; Vaisy et al. 2011; Araújo
et al. 2013), Ferrante et al. (2000) used a transgenic mouse
model of Huntington’s Disease, Op’t Eijnde et al. (2006)
studied Goto-Kakizaki rats (a animal model of inherited
T2DM), and Nicastro et al. (2012) used rats treated with
dexamethasone. Four studies examined the effects of cre-
atine supplementation associated with exercise training on
glucose metabolism (Souza et al. 2006; Freire et al. 2008;
Vaisy et al. 2011; Araújo et al. 2013), and seven studies
Table 1 Search strategy
The search strategy consists of two separate components and each component consists of the key words related to “creatine supplementation”
and the key words related to “glucose metabolism” individually. The key words in each component were linked using “OR” as a Boolean func-
tion, and the results of the two sections were combined by utilizing the “AND” Boolean in final search
Search engines Components Search keywords Number of search results
PubMed Component 1: creatine supplementation ((“creatine”[Title]) OR “creatine
supplementation”[Title])
n = 8758
Component 2: glucose metabolism (((((((((((“diabetes”[Title]) OR “diabetic”[Title])
OR “glycemia”[Title]) OR “fasting
blood glucose”[Title]) OR “fasting blood
sugar”[Title]) OR “blood glucose”[Title]) OR
“insulin”[Title]) OR “insulin resistance”[Title])
OR “serum insulin”[Title]) OR “impaired
glucose tolerance”[Title]) OR “impaired
fasting glucose”[Title]) OR “glucose
homeostasis”[Title]
n = 348,675
Component 1 and component 2: creatine sup-
plementation and glucose metabolism
(((((((((((((“diabetes”[Title]) OR
“diabetic”[Title]) OR “glycemia”[Title])
OR “fasting blood glucose”[Title]) OR
“fasting blood sugar”[Title]) OR “blood
glucose”[Title]) OR “insulin”[Title]) OR
“insulin resistance”[Title]) OR “serum
insulin”[Title]) OR “impaired glu-
cose tolerance”[Title]) OR “impaired
fasting glucose”[Title]) OR “glucose
homeostasis”[Title])) AND ((“creatine”[Title])
OR “creatine supplementation”[Title])
n = 77
Scopus Component 1: creatine supplementation ((“creatine”[Title]) OR “creatine
supplementation”[Title])
n = 9775
Component 2: glucose metabolism (((((((((((“diabetes”[Title]) OR “diabetic”[Title])
OR “glycemia”[Title]) OR “fasting
blood glucose”[Title]) OR “fasting blood
sugar”[Title]) OR “blood glucose”[Title]) OR
“insulin”[Title]) OR “insulin resistance”[Title])
OR “serum insulin”[Title]) OR “impaired
glucose tolerance”[Title]) OR “impaired
fasting glucose”[Title]) OR “glucose
homeostasis”[Title]
n = 426,409
Component 1 and component 2: creatine sup-
plementation and glucose metabolism
(((((((((((((“diabetes”[Title]) OR
“diabetic”[Title]) OR “glycemia”[Title])
OR “fasting blood glucose”[Title]) OR
“fasting blood sugar”[Title]) OR “blood
glucose”[Title]) OR “insulin”[Title]) OR
“insulin resistance”[Title]) OR “serum
insulin”[Title]) OR “impaired glu-
cose tolerance”[Title]) OR “impaired
fasting glucose”[Title]) OR “glucose
homeostasis”[Title])) AND ((“creatine”[Title])
OR “creatine supplementation”[Title])
n = 93

C. L. Pinto et al.
1 3
adopted creatine supplementation alone (Young and Young
2002; Rooney et al. 2002; Ju et al. 2005; Souza et al. 2006;
Op’t Eijnde et al. 2006; Eijnde et al. 2001; Nicastro et al.
2012). Studies that involved exercise training employed
swimming (Souza et al. 2006; Freire et al. 2008; Vaisy
et al. 2011) or treadmill running (Araújo et al. 2013). The
dose of creatine supplementation was described as the
percentage of the amount of supplement in the diet (from
1 to 13 %) or as the daily dose (ranging from 300 to 5 g/
kg). Two studies (Souza et al. 2006; Araújo et al. 2013)
used a “loading stage” protocol (i.e., higher dose during 1
week) followed by a “maintenance stage” (i.e., lower dose
after “loading” to maintain creatine levels increased), and
the remaining studies maintained the same dose protocol
during all the experiments (Ferrante et al. 2000; Young
and Young 2002; Rooney et al. 2002; Ju et al. 2005; Op’t
Eijnde et al. 2006; Freire et al. 2008; Eijnde et al. 2001;
Vaisy et al. 2011; Nicastro et al. 2012). The duration of the
interventions ranged from 5 to 94 days.
The three studies that assessed the effects of creatine
supplementation on glucose metabolism in insulin resistant
animals (Ferrante et al. 2000; Op’t Eijnde et al. 2006; Nica-
stro et al. 2012) showed conflicting results. Ferrante et al.
(2000) and Op’t Eijnde et al. 2006 found beneficial effects
of creatine, including attenuation of insulin concentra-
tion and improved sensitivity to insulin in extrapancreatic
Records identified through database
searching in Pubmed (n = 77) and
Scopus (n = 93)
Screening
Included Eligibility Identification
Additional records identified
through other sources
(n = 6)
Records after duplicates removed
(n = 102)
Records screened
(n = 96)
Records excluded (n = 70)
Reason:
Irrelevant articles (n = 70)
Full-text articles assessed
for eligibility
(n = 26)
Full-text articles excluded
(n = 14)
Reasons:
Cross- sectionalstudies (n
= 2)
In vitro studies (n = 1)
Studies with other animal
samples (n = 1)
Studies which glucose
metabolism was not
included in the outcomes
(n = 5)
Intervention was not
creatine supplementation
associated or not with
exercise training (n = 2)
Articles in other languages
(n = 2)
Studies which participants
were vegetarian (n = 1)
Studies included in
qualitative synthesis
(n = 12)
Studies included in review
(n = 19, in which 7 were
manually searched in the
references and included)
Fig. 1 PRISMA 2009 flow diagram of the structured literature review

Creatine supplementation and glycemic control: a systematic review
1 3
Table 2 Characteristics of the included animal studies
Study (year) Methods Target population nIntervention/
duration of the
intervention
Dose Glucose metabolism
outcomes
Results and p
values
Relevant outcomes Results and p values
Ferrante et al.
(2000)
Controlled Transgenic Hun-
tington’s disease
R6/2 mice
25(C)/25(Cr) Oral administration
of Cr/21 days
of age
Diets supplemented
with 1, 2, or 3 %
of Cr
Glucose tolerance aWithin: NM and
bBetween: S (↑ in
2 %, p < 0.01)
Survival Within: S (↑ in
3 %, p < 0.0002)
and Between: S
(↑ in 1 and 2 %,
p < 0.0001)
Rotarod perfor-
mance
Within: NM and
Between: S (↑
in 1, and 2 %,
p < 0.001)
Body weight Within: S (↑ in 2 %,
p < 0.01) and
Between: S (↑ in 1
and 3 %, p < 0.02)
and S (↑ in 2 %,
p < 0.01)
Eijnde et al. (2001) Controlled Male Wistar rats NM(C)/NM(Cr) Oral administration
of Cr monohy-
drate/5 days
Powdered rat chow
containing 5 % of
Cr monohydrate
Muscle GLUT4
content
Within: NM and
Between: NS in
either muscle
type
Muscle glycogen
content
Within: NM and
Between: S (↑ in
Cr in red gastroc-
nemius and soleus,
p < 0.05); NS
(white gastrocne-
mius)
Glucose transport
rate
Within: NM and
Between: NS in
either muscle
type
Muscle Cr and PCr
content
Within: NM and
Between: S (↑
in Cr in soleus,
p < 0.05); NS (red
gastrocnemius and
white gastrocne-
mius)
Plasma insulin Within: NM and
Between: NS in
either muscle
type
Muscle total Cr
content
Within: NM and
Between: S (↑ in
Cr in red gastroc-
nemius and soleus,
p < 0.05); NS
(white gastrocne-
mius)
Blood glucose Within: NM and
Between: NS in
either muscle
type
Muscle ATP
content
Within: NM and
Between: S (↓
in Cr in white
gastrocnemius,
p < 0.05); NS (red
gastrocnemius and
soleus)
Muscle water
content
Within: NM and
Between: NS in
either muscle type

C. L. Pinto et al.
1 3
Table 2 continued
Study (year) Methods Target population nIntervention/
duration of the
intervention
Dose Glucose metabolism
outcomes
Results and p
values
Relevant outcomes Results and p values
Muscle glucose
uptake after insu-
lin perfusion
Within: NM and
Between: NS in
either muscle
type
Glycogen synthase
activity
Within: NM and
Between: NS in
either muscle type
Muscle glucose
uptake after cre-
atine perfusion
Within: NM and
Between: NS in
either muscle
type
Plasma creatine Within: NM and
Between: S (↑ in
Cr 1 h after feed-
ing, p < 0.05)
Glycogen synthesis
rate
Within: NM and
Between: NS in
either muscle type
Ju et al. (2005) Controlled Female Wistar rats 7(C)/7(Cr) Oral administration
of Cr monohy-
drate/3 weeks
Chow containing
2 % of Cr mono-
hydrate
Extensor digitorum
longus, triceps,
and epitrochlearis
muscle GLUT4
contents
Within: NM and
Between: S (↑ in
Cr, p < 0.05)
Body weight Within: NM and
Between: NS
Triceps GLUT4
mRNA
Within: NM and
Between: S (↑ in
Cr, p < 0.05)
Extensor digitorum
longus muscle
Cr, PCr, total Cr
contents, and
[PCr]/[total Cr]
ratio
Within: NM and
Between: NS
Insulin-stimulated
glucose transport
in epitrochlearis
muscles
Within: NM and
Between: S (↑ in
Cr, p < 0.005)
AMPK phosphoryl-
ation in extensor
digitorum longus
muscle
Within: NM and
Between: S (↑ in
Cr, p < 0.05)
Extensor digitorum
longus muscle
ATP and AMP
content
Within: NM and
Between: NS
Acetyl-CoA carbox-
ylase phosphoryl-
ation in extensor
digitorum longus
muscle
Within: NM and
Between: S (↑ in
Cr, p < 0.05)
Extensor digitorum
longus muscle
creatinine
content
Within: NM and
Between: S (↑ in
Cr, p < 0.005)
Myocyte enhancer
factor 2 content
Within: NM and
Between: S (↑ in
Cr, p < 0.05)
Glycogen content
of epitrochlearis
muscles
Within: NM and
Between: S (↑ in
Cr, p < 0.05)
Myocyte enhancer
factor 2-DNA-
binding activity
Within: NM and
Between: S (↑ in
Cr, p < 0.05)

Creatine supplementation and glycemic control: a systematic review
1 3
Table 2 continued
Study (year) Methods Target population nIntervention/
duration of the
intervention
Dose Glucose metabolism
outcomes
Results and p
values
Relevant outcomes Results and p values
Souza et al. (2006) Controlled Male Wistar rats G1: 18(C)
G2: 18 (Trained)
G3: 18 (Cr)
G4: 18
(Trained + Cr)
Oral administra-
tion of Cr and/
or Swim-
ming/8 weeks
5 g/kg of body
weight of Cr for
7 days (loading
phase)/1 g/kg of
body weight of Cr
for 7 days (main-
tenance phase)
Plasma glucose
levels
Within: NM and
Between: S (↓
in G3 dur-
ing 1–4 week,
p < 0.05) and
(↓ in G4 dur-
ing 1–8 week,
p < 0.05)
Body weight Within: NM and
Between: S (↑
in G3 and G4,
p < 0·.05)
Maximum toler-
ated load
Within: NM and
Between: S (↑
in G4 dur-
ing 1–8 week,
p < 0.05)
Plasma lactate
levels
Within: NM and
Between: S (↓
in G3 dur-
ing 1–2 week,
p < 0.05) and
(↓ in G4 dur-
ing 1–8 week,
p < 0.05)
Op’t Eijnde et al.
(2006)
Controlled Male Goto-Kaki-
zaki rats
G1: 6 (C 6-week
age)
G2: 6 (C 14-week
age)
G3: 6 (Cr 6-week
age)
G4: 6 (Cr 14-week
age)
Oral administration
of Cr monohy-
drate/8 weeks
Normal rodent pel-
lets enriched with
2 % Cr
Basal blood
d-glucose concen-
tration
Within: NM and
Between: NS
Body weight Within: NM and
Between: NS
Blood d-glucose
concentration 5
and 120 min after
glucose tolerance
test
Within: NM and
Between: NS
Muscle Cr content Within: NM and
Between: S (↑ in
G3, p < 0.05)
Plasma insulin
concentration
Within: NM and
Between: S (↓
in G3, and G4,
p < 0.05)
Muscle glycogen
content
Within: NM and
Between: NS
Insulinogenic index
before and after
administration
of exogenous
d-glucose
Within: NM and
Between: S (↓
in G3, and G4,
p < 0.01)

C. L. Pinto et al.
1 3
Table 2 continued
Study (year) Methods Target population nIntervention/
duration of the
intervention
Dose Glucose metabolism
outcomes
Results and p
values
Relevant outcomes Results and p values
Araújo et al. (2013) Controlled Male Wistar rats G1: 10 (C seden-
tary)
G2: 10 (Cr seden-
tary)
G3: 10 (Trained)
G4: 10 (Cr trained)
Oral administration
of Cr mono-
hydrate or/and
training (tread-
mill)/8 weeks
Diet supplemented
with 13 % Cr for
7 days (load-
ing phase)/diet
supplemented
with 2 % Cr for
55 days (mainte-
nance phase)
Glucose uptake Within: NM and
Between: NS
Body weight Within: NM and
Between: S (↓
in G3, and G4,
p < 0.05)
Food intake Within: NM and
Between: NS
Glucose oxidation Within: NM and
Between: S (↑
in G2 and G4,
p < 0.05)
Hydric intake Within: NM and
Between: S (↑ in
G4, p < 0.05)
Glycogen synthesis Within: NM and
Between: NS
Glucose AUC dur-
ing the OGTT
Within: NM and
Between: S (↓ in
G4, p < 0.05)
Glycogen concen-
tration
Within: NM and
Between: NS
Lactate production
by the soleus
muscle
Within: NM and
Between: S (↓ in
G4, p < 0.05)
Young and Young
(2002)
Random-controlled Male Sprague–
Dawley rats
4(C)/4(Cr) Oral administration
of Cr monohy-
drate/5 weeks
300 mg/kg body
weight in gelatin
daily
Insulin-stimulated
2-deoxyglucose
uptake
Within: S (↑ in C
and Cr, p < 0.01)
and Between: NS
Body weight Within: NM and
Between: NS
Epitrochlearis mus-
cle weight
Within: NM and
Between: NS
Basal rates of
glucose uptake
Within: NM and
Between: NS
Free Cr from plan-
taris muscle
Within: NM and
Between: S (↑ in
Cr, p < 0.01)
TCr from plantaris
muscle
Within: NM and
Between: S (↑ in
Cr, p < 0.05)
PCr Within: NM and
Between: NS
Insulin-stimulated
rates of glucose
uptake
Within: NM and
Between: NS
PCr/TCr ratio Within: NM and
Between: S (↓ in
Cr, p < 0.05)
ATP concentration Within: NM and
Between: S (↑ in
Cr, p = 0.05)

Creatine supplementation and glycemic control: a systematic review
1 3
Table 2 continued
Study (year) Methods Target population nIntervention/
duration of the
intervention
Dose Glucose metabolism
outcomes
Results and p
values
Relevant outcomes Results and p values
Rooney et al.
(2002)
Random-controlled Male Wistar rats 8(C)/8(Cr) Oral administration
of Cr hydrate/2,
4, or 8 weeks
20 g of standard
chow diet per rat
per day of which
2 % by weight
was Cr
Fasting plasma
glucose levels
Within: NM and
Between: NS (2,
4, or 8 weeks)
Body weight Within: NM and
Between: NS (2, 4,
or 8 weeks)
Plasma glucose
levels after an oral
glucose load
Within: NM and
Between: NS (2,
4, or 8 weeks)
Pancreatic Cr
content
Within: NM and
Between: S (↑
in Cr after 2, 4,
and 8 weeks,
p < 0.0001)
Fasting plasma
insulin levels
Within: NM and
Between: NS
(2, or 4 weeks)
and S (↑ in Cr
after 8 weeks,
p = 0.01)
Quadriceps muscle
Cr content
Within: NM and
Between: NS (2, 4,
or 8 weeks)
Quadriceps glyco-
gen content
Within: NM and
Between: NS (2, 4,
or 8 weeks)
Plasma insulin
levels after an oral
glucose load
Within: NM and
Between: NS (2,
4, or 8 weeks)
Glycogen synthase
activity in the
quadriceps
muscles
Within: NM and
Between: NS (2, 4,
or 8 weeks)
Glycogen
phosphorylase-α
activity in the
quadriceps
muscles
Within: NM and
Between: NS (2, 4,
or 8 weeks)

C. L. Pinto et al.
1 3
Table 2 continued
Study (year) Methods Target population nIntervention/
duration of the
intervention
Dose Glucose metabolism
outcomes
Results and p
values
Relevant outcomes Results and p values
Freire et al. (2008) Random-controlled Male Wistar rats G1: 9 (C/seden-
tary/4 weeks of
duration)
G2: 6 (C/
trained/4 weeks
of duration)
G3: 10 (Cr/seden-
tary/4 weeks of
duration)
G4: 8 (Cr/
trained/4 weeks
of duration)
G5: 10 (C/seden-
tary/8 weeks of
duration)
G6: 7 (C/
trained/8 weeks
of duration)
G7: 8 (Cr/seden-
tary/8 weeks of
duration)
G8: 7 (Cr/
trained/8 weeks
of duration)
Oral administration
of Cr or/and train-
ing (swimming)/4
or 8 weeks
Normal rodent pel-
lets enriched with
2 % Cr
OGTT Within: NS and
Between: NS
Body weight Within: NM and
Between: NS
Liver glycogen
content
Within: NS and
Between: NS
Quadriceps glyco-
gen content
Within: NS and
Between: NS

Creatine supplementation and glycemic control: a systematic review
1 3
Table 2 continued
Study (year) Methods Target population nIntervention/
duration of the
intervention
Dose Glucose metabolism
outcomes
Results and p
values
Relevant outcomes Results and p values
Vaisy et al. (2011) Random-controlled Male Wistar rats G1: 10 (C)
G2: 16 (Cafeteria
diet)
G3: 15 (Cafeteria
diet + training)
G4: 19 (Cr + caf-
eteria diet)
G5: 9 (Cr + caf-
eteria
diet + training)
Cafeteria diet and/
or oral admin-
istration of Cr
monohydrate and/
or training (swim-
ming)/12 weeks
Cafeteria diet
enriched with
2.5 % Cr
Fasting blood
glucose concen-
tration
Within: NM and
Between: NS
Body weight Within: NM and
Between: S (↑ in
G2, G3, G4, and
G5, p < 0.05)
Fasting plasma
insulin level
Within: NM and
Between: S (↑ in
G2, p < 0.05) and
S (↓ in G3 and
G5, p < 0.05)
IMLC in soleus
and extensor
digitorum longus
muscles
Within: NM and
Between: S (↑ in
G2, p < 0.05)
FAT/CD36 protein
content in muscle
soleus
Within: NM and
Between: S (↓ in
G3, G4, and G5,
p < 0.05)
Whole-body glu-
cose tolerance
Within: NM and
Between: S (↓ in
G2, G3, G4, and
G5, p < 0.05)
Fecal fat Within: NM and
Between: S (↑ in
G4, p < 0.05)
Triglyceride
concentration in
blood and liver
Within: NM and
Between: S (↑ in
G4, p < 0.05)
Insulin-stimulated
muscle glucose
transport
Within: NM and
Between: S (↓
in G2, and G4,
p < 0.05)
Muscle-free Cr
content
Within: NM and
Between: NS
PCr content Within: NM and
Between: NS
Glycogen content Within: NM and
Between: NS

C. L. Pinto et al.
1 3
Table 2 continued
Study (year) Methods Target population nIntervention/
duration of the
intervention
Dose Glucose metabolism
outcomes
Results and p
values
Relevant outcomes Results and p values
Nicastro et al.
(2012)
Random-controlled Male Wistar rats G1: 6 (DXM)
G2: 6 (C)
G3: 6
(DXM + Cr)
G4: 6 (Cr)
DXM
and Cr were given
daily via drinking
water/7 days
DXM (5 mg/kg/day)
and Cr (5 g/kg/
day) were given
daily via drinking
water
Serum
glucose concentra-
tion
Within: NM and
Between: S (↑ in
G3, p < 0.001)
Body weight Within: NM and
Between: S (↓
in G2 and G4,
p < 0.05)
Weight throughout
the study
Within: NM and
Between: S (↓
in G1 and G3,
p < 0.05)
Serum insulin
concentration
Within: NM and
Between: S (↑ in
G3, p < 0.001)
Plantaris and
extensor
digitorum longus
muscle mass
Within: NM and
Between: S (↓
in G1 and G3,
p < 0.05)
GLUT4 transloca-
tion
Within: NM and
Between: S (↓ in
G3, p < 0.01)
Muscle dry:wet
weight ratio
Within: NM and
Between: NS
Phospho-Ser473-
Akt protein
levels
Within: NM and
Between: S (↓ in
G3, p < 0.001)
GLUT4 protein
content
Within: NM and
Between: NS
Total-FoxO3a pro-
tein expression
Within: NM and
Between: NS
Phospho-Ser253-
FoxO3a protein
expression
Within: NM and
Between: S (↓
in G1 and G3,
p < 0.01)
HOMA-IR Within: NM and
between: S (↑ in
G3, p < 0.001)
MuRF-1 protein
expression
Within: NM and
Between: S (↑
in G1 and G3,
p < 0.001)
AMPK adenosine monophosphate activated protein kinase, ATP adenosine triphosphate, AUC area under the curve, C control group, Cr creatine, DXM dexamethasone, FAT fatty acid translocase,
G group, GLUT glucose transporter, HK hexokinase, HOMA-IR insulin resistance index, IMLC intramyocellular lipid content, LDH lactate dehydrogenase, mRNA messenger RNA, NM not men-
tioned, NS not significant, OGTT oral glucose tolerance test, PCr phosphocreatine, RNA ribonucleic acid, S significant, TCr total creatine
a “Within”, refers to within groups comparisons
b “Between” refers to between groups comparisons

Creatine supplementation and glycemic control: a systematic review
1 3
Table 3 Characteristics of the included human studies
Study (year) Methods Target population nIntervention/dura-
tion of the interven-
tion
Dose Glucose metabo-
lism outcomes
Results and p
values
Relevant outcomes Results and p values
Op’t Eijnde et al.
(2001)
Double-blind,
placebo-con-
trolled trial
Young and
healthy subjects
(men and
women)
11(C)/11(Cr) Oral administration
of Cr monohy-
drate and/or Reha-
bilitation program
of 10 weeks
after 2 weeks of
immobilization
of 1 leg (a cast
from groin to
ankle)/12 weeks
Week 1–2: 5 g of
Cr, 4 times a day
Week 3–5: 5 g of
Cr, 3 times a day
Week 6 on: 5 g of
Cr per day
Muscle GLUT4
content (immobi-
lized leg)
During immobili-
zation:
aWithin: S (↓ in
C, p < 0.05) and
bBetween: S (↓
in C, p < 0.05)
and (↑ in Cr,
p < 0.05)
During rehabilita-
tion:
Within: NS and
Between: S (↑ in
Cr, p < 0.05)
Muscle glycogen
concentration
(immobilized
leg)
During immobiliza-
tion:
Within: NS and
Between: NS
During rehabilita-
tion:
Within: S (↑ in Cr,
p < 0.05) and
Between: S (↑ in
Cr after 3 weeks,
p < 0.05)
S (↑ in Cr and C
after 7 weeks,
p < 0.05)
Muscle PCr
concentration
(immobilized
leg)
During immobiliza-
tion:
Within: (↓ in C,
p < 0.05) and
Between: S (↓
in C and ↑ in Cr,
p < 0.05)
During rehabilita-
tion:
Within: NS and
Between: S (↑ in
Cr, p < 0.05)
Muscle free Cr
concentration
(immobilized
leg)
During immobiliza-
tion:
Within: S (↑ in C
and Cr,
p < 0.05) and
Between: NS
During rehabilita-
tion:
Within: S (↑ in C
and Cr,
p < 0.05) and
Between: NS

C. L. Pinto et al.
1 3
Table 3 continued
Study (year) Methods Target population nIntervention/dura-
tion of the interven-
tion
Dose Glucose metabo-
lism outcomes
Results and p
values
Relevant outcomes Results and p values
Muscle total Cr
concentration
(immobilized
leg)
During immobiliza-
tion:
Within: S (↑ in Cr,
p < 0.05) and
Between: S (↑
in Cr,
p < 0.05)
During rehabilita-
tion:
Within: S (↑ in Cr,
p < 0.05) and
Between: S (↑ in
Cr, p < 0.05)
Plasma insulin
response after
OGTT
Within: NS and
Between: NS
Gualano et al.
(2008)
Double-blind, ran-
domized placebo-
controlled trial
Healthy, seden-
tary, eutrophic,
and non-vege-
tarian, subjects
(men)
10(C)/12(Cr) Oral administration
of Cr monohy-
drate and/or Mod-
erate intensity
aerobic
Training/12 weeks
Loading phase (the
first week): 0.3 g/
kg of body weight
of Cr per day
Maintenance phase
(next 11 weeks):
0.15 g/kg of body
weight of Cr per
day
Plasma glucose
concentration
after OGTT
After 4 weeks:
Within: NS and
Between: NS
After 8 weeks:
Within: NS and
Between: NS
After 12 weeks:
Within: NS and
Between: NS
– –
Glucose AUC after
OGTT
Within: S (↓
in Cr and C,
p = 0.005) and
Between: S (↓ in
Cr, p = 0.034)
HOMA index After 4 weeks:
Within: NS and
Between: NS
After 8 weeks:
Within: NS and
Between: NS
After 12 weeks:
Within: NS and
Between: NS

Creatine supplementation and glycemic control: a systematic review
1 3
Table 3 continued
Study (year) Methods Target population nIntervention/dura-
tion of the interven-
tion
Dose Glucose metabo-
lism outcomes
Results and p
values
Relevant outcomes Results and p values
Fasting insulin After 4 weeks:
Within: NS and
Between: NS
After 8 weeks:
Within: NS and
Between: NS
After 12 weeks:
Within: NS and
Between: NS
Gualano et al.
(2011)
Double-blind, ran-
domized placebo-
controlled trial
Subjects pre-
diagnosed with
type 2 diabetes,
physically inac-
tive for at least
1 year, and with
BMI ≥ 30 kg/
m2
12(C)/13(Cr) Oral administration
of Cr mono-
hydrate and/
or Moderate
intensity aerobic
training combined
with strength-
ening exer-
cises/12 weeks
5 g of Cr per day HbA1c concentra-
tions
Within: S (↓ in Cr,
p = 0.0001) and
Between: S (↓ in
Cr, p = 0.004)
Muscle PCr
content
Within: NM and
Between: S (↑ in
Cr, p = 0.03)
Glycemia during
MTT
Within: NS and
Between: S (↓
in Cr in 0 min,
p = 0.001), S (↓
in Cr in 30 min,
p = 0.004),
and S (↓ in
Cr in 60 min,
p = 0.003)
1-RM leg press Within: S (↑ in Cr
and C, p = 0.007)
and Between: NS
Insulin concentra-
tions during
MTT
Within: NS and
Between: NS
1-RM bench press Within: S (↑ in Cr
and C, p < 0.01)
and Between: NS
C-peptide concen-
trations during
MTT
Within: NS and
Between: NS
Low back strength Within: S (↑ in Cr
and C, p = 0.03)
and Between: NS
Delta AUC for
glucose concen-
tration
Within: NS and
Between: S (↓ in
Cr, p = 0.05)
Handgrip strength Within: NS and
Between: NS
Delta AUC for
insulin concen-
tration
Within: NS and
Between: NS
Timed-stands test Within: S (↑ in Cr
and C, p < 0.001)
and Between: NS
Delta AUC for
C-peptide con-
centration
Within: NS and
Between: NS
Timed-up-and-go
test
Within: NS and
Between: NS
HOMA-IR index Within: NS and
Between: NS
VO2- VAT Within: S (↑ in Cr
and C, p < 0.001)
and Between: NS

C. L. Pinto et al.
1 3
Table 3 continued
Study (year) Methods Target population nIntervention/dura-
tion of the interven-
tion
Dose Glucose metabo-
lism outcomes
Results and p
values
Relevant outcomes Results and p values
HOMA-β index Within: NS and
Between: NS
VO2-RCP Within: S (↑ in Cr
and C, p = 0.08)
and Between: NS
Glucose/insulin
index
Within: NS and
Between: NS
VO2max Within: NS and
Between: NS
Muscle GLUT-4
content
Within: NS and
Between: NS
Total training
volume
Within: NM and
Between: NS
Membrane
GLUT-4 content
Within: S (↑ in Cr
and C, p < 0.001)
and Between:
S (↑ in Cr,
p = 0.05)
Blood lipoproteins Within: NS and
Between: NS
Membrane-total
GLUT-4 content
ratio
Within: S (↑ in Cr
and C, p < 0.001)
and Between:
S (↑ in Cr,
p = 0.03)
Blood apolipopro-
teins
Within: NS and
Between: NS
Body composition
variables
Within: NS and
Between: NS
Van Loon et al.
(2004)
Double-blind,
placebo-con-
trolled trial
Young, and
non-vegetarian,
subjects (men)
10(C)/9(Cr) Oral administration
of Cr monohy-
drate/6 weeks
Loading phase
(day 1–5): 5 g
of Cr + 15 g of
glucose + 10 g of
maltodextrin, 4
times a day.
Maintenance phase
(day 6 on): 2 g
of Cr + 15 g of
glucose + 10 g
of maltodextrin
per day
Fasting plasma
insulin concen-
trations
Within: NS and
Between: NS
Muscle free Cr
content
After loading phase:
Within: S (↑ in Cr,
p < 0.05) and
Between: NS
After maintenance
phase:
Within: S (↑ in Cr,
p < 0.05) and
Between: NS
Muscle PCr
content
After loading phase:
Within: S (↑ in Cr,
p < 0.05) and
Between: S (↑ in
Cr, p < 0.05)
After maintenance
phase:
Within: S (↑ in Cr,
p < 0.05) and
Between: NS

Creatine supplementation and glycemic control: a systematic review
1 3
Table 3 continued
Study (year) Methods Target population nIntervention/dura-
tion of the interven-
tion
Dose Glucose metabo-
lism outcomes
Results and p
values
Relevant outcomes Results and p values
Muscle total Cr
content
After loading phase:
Within: S (↑ in Cr,
p < 0.05) and
Between: S (↑ in
Cr, p < 0.05)
After maintenance
phase:
Within: S (↑ in Cr,
p < 0.05) and
Between: NS
GLUT4 mRNA
content
After loading
phase:
Within: NS and
Between: NS
After maintenance
phase:
Within: NS and
Between: NS
Muscle ATP
content
After loading phase:
Within: NS and
Between: NS
After maintenance
phase:
Within: NS and
Between: NS
Muscle glycogen
content
After loading phase:
Within: NS and
Between: S (↑ in
Cr, p < 0.05)
After maintenance
phase:
Within: S (↑ in Cr,
p < 0.05) and
Between: NS
Muscle glycogen
content (relative
change)
After loading phase:
Within: S (↑ in Cr,
p < 0.05) and
Between: S (↑ in
Cr, p < 0.05)
After maintenance
phase:
Within: NS and
Between: NS
Muscle GLUT4
protein content
After loading
phase:
Within: NS and
Between: NS
After maintenance
phase:
Within: NS and
Between: NS
Glycogen synthase
mRNA content
After loading phase:
Within: NS and
Between: NS
After maintenance
phase:
Within: NS and
Between: NS

C. L. Pinto et al.
1 3
Table 3 continued
Study (year) Methods Target population nIntervention/dura-
tion of the interven-
tion
Dose Glucose metabo-
lism outcomes
Results and p
values
Relevant outcomes Results and p values
Glycogen mRNA
content
After loading phase:
Within: NS and
Between: NS
After maintenance
phase:
Within: NS and
Between: NS
Newman et al.
(2003)
Single-blind,
placebo-con-
trolled trial
Healthy active,
but untrained
Subjects (men)
9(C)/10(Cr) Oral administration
of Cr monohy-
drate/ 38 days
Loading phase
(day 1–5): 5 g of
Cr + 3.75 g of
glucose + 4 times
a day.
Maintenance phase
(day 6 on): 3 g
of Cr + 3 g of
glucose per day
Plasma glucose
concentrations
during OGTT
After loading
phase:
Within: NM and
Between: NS
After maintenance
phase:
Within: NM and
Between: NS
Muscle total Cr
content
After loading phase:
Within: NM and
Between: S (↑ in
Cr, p < 0.05)
After maintenance
phase:
Within: NM and
Between: S (↑ in
Cr, p < 0.05)
Plasma insulin
concentrations
during OGTT
After loading
phase:
Within: NM and
Between: NS
After maintenance
phase:
Within: NM and
Between: NS
Muscle ATP
content
After loading phase:
Within: NM and
Between: NS
After maintenance
phase:
Within: NM and
Between: NS
Fasting plasma
insulin
After loading
phase:
Within: NM and
Between: NS
After maintenance
phase:
Within: NM and
Between: NS
Glucose-insulin
index
After loading
phase:
Within: NM and
Between: NS
After maintenance
phase:
Within: NM and
Between: NS
Muscle glycogen
content
After loading phase:
Within: NM and
Between: NS
After maintenance
phase:
Within: NM and
Between: NS

Creatine supplementation and glycemic control: a systematic review
1 3
Table 3 continued
Study (year) Methods Target population nIntervention/dura-
tion of the interven-
tion
Dose Glucose metabo-
lism outcomes
Results and p
values
Relevant outcomes Results and p values
Index of insulin
sensitivity during
OGTT
After loading
phase:
Within: NM and
Between: NS
After maintenance
phase:
Within: NM and
Between: NS
Derave et al. (2003) Double-blind, rand-
omized, placebo-
controlled trial
Healthy subjects
(men and
women)
11(C)/11
(Cr)/11(Cr + pro-
tein)
Oral administration
of Cr monohy-
drate and/or Reha-
bilitation program
of 6 weeks after
2 weeks of immo-
bilization of 1 leg
(a cast from groin
to ankle)/8 weeks
Week 1–2: 5 g of
Cr, 4 times a day
Week 3 on: 2.5 g
of Cr
per day, 40 g of
protein per day,
and 6.7 g of
amino acids per
day
Protein expres-
sion of GLUT4
(immobilized
leg)
During immobili-
zation:
Within: S (↓ in C
and Cr, p < 0.05)
and Between: NS
During rehabilita-
tion:
Within: S (↑ in Cr
and Cr + protein,
p < 0.05) and
Between: S (↑ in
Cr and Cr + pro-
tein, p < 0.05)
Muscle glycogen
content (immobi-
lized leg)
During immobiliza-
tion:
Within: NS and
Between: NS
During rehabilita-
tion:
Within: S (↑ in Cr
and Cr + protein,
p < 0.05) and
Between: S (↑ in
Cr and Cr + pro-
tein, p < 0.05)
Muscle free Cr
concentration
(immobilized
leg)
During immobiliza-
tion:
Within: S (↑ in
Cr + protein,
p < 0.05) and
Between: NS
During rehabilita-
tion:
Within: S (↑ in Cr
and Cr + protein,
p < 0.05) and
Between: NS
Glucose AUC in a
2-h OGTT
During immobili-
zation:
Within: NS and
Between: NS
During rehabilita-
tion:
Within: S (↑ in
Cr + protein,
p < 0.05) and
Between: S (↑
in Cr + protein,
p < 0.05)
Muscle PCr
concentration
(immobilized
leg)
During immobiliza-
tion:
Within: NS and
Between: NS
During rehabilita-
tion:
Within: NS and
Between: S (↑
in Cr + protein,
p < 0.05)

C. L. Pinto et al.
1 3
Table 3 continued
Study (year) Methods Target population nIntervention/dura-
tion of the interven-
tion
Dose Glucose metabo-
lism outcomes
Results and p
values
Relevant outcomes Results and p values
Muscle total Cr
concentration
(immobilized
leg)
During immobiliza-
tion:
Within: NS and
Between: NS
During rehabilita-
tion:
Within: S (↑ in Cr
and Cr + protein,
p < 0.05) and
Between: NS
Muscle fiber-type
composition
During immobiliza-
tion:
Within: NS and
Between: NS
During rehabilita-
tion:
Within: NS and
Between: NS
Plasma insulin
levels
During immobili-
zation:
Within: NS and
Between: NS
During rehabilita-
tion:
Within: NS and
Between: NS
Maximal isometric
knee extension
torque (immobi-
lized leg)
During immobiliza-
tion:
Within: S (↓ in C, Cr
and Cr + protein,
p < 0.05) and
Between: NS
During rehabilita-
tion:
Within: S (↑ in C
and Cr + protein,
p < 0.05) and
Between: NS
Recovery indexes
extensor muscles
(immobilized
leg)
During immobiliza-
tion:
Within: NS and
Between: NS
During rehabilita-
tion:
Within: S (↑ in Cr
and Cr + protein,
p < 0.05) and
Between: NS

Creatine supplementation and glycemic control: a systematic review
1 3
Table 3 continued
Study (year) Methods Target population nIntervention/dura-
tion of the interven-
tion
Dose Glucose metabo-
lism outcomes
Results and p
values
Relevant outcomes Results and p values
Body weight During immobiliza-
tion:
Within: S (↑ in Cr
and Cr + protein,
p < 0.05) and
Between: NS
During rehabilita-
tion:
Within: S (↑ in C, Cr
and Cr + protein,
p < 0.05) and
Between: NS
Alves et al. (2012) Double-blind, ran-
domized placebo-
controlled trial
Subjects pre-
diagnosed with
type 2 diabetes,
physically inac-
tive for at least
1 year, and with
BMI ≥ 30 kg/
m2
12(C)/13(Cr) Oral adminis-
tration of Cr
monohydrate
and/or moderate
intensity aerobic
training combined
with strength-
ening exer-
cises/12 weeks
5 g of Cr per day IR-β expression Within: NS and
Between: NS
– –
AKT-1 expression Within: NS and
Between: NS
MAPK p42/44
expression
Within: NS and
Between: NS
AMPK-α expres-
sion
Within: NS and
Between: NS
Correlation
between changes
in AMPK-α lev-
els and changes
in GLUT-4
translocation
r = 0.71
p < 0.001
Correlation
between changes
in AMPK-α
expression and
changes in Hb1Ac
levels
r = −0.68
p < 0.001
Correlation
between changes
in Hb1Ac levels
and GLUT-4
translocation
r = −0.89
p < 0.001

C. L. Pinto et al.
1 3
tissues. Although they used different rodent models, both
are type 2 diabetics, intervention period (8 weeks), and a
similar dose of creatine (2 %). In contrast, Nicastro et al.
(2012) induced severe muscle wasting and insulin resist-
ance in rats by giving them dexamethasone, and after only
7 days of intervention, they found that creatine supple-
mentation aggravated the dexamethasone-induced insulin
resistance. The authors attributed the discrepancy regarding
the effects of creatine on glucose metabolism to species-
specific responses to creatine supplementation. In fact, Tar-
nopolsky and colleagues (Tarnopolsky et al. 2003) showed
that creatine could induce hepatitis in mice, but not in rats,
suggesting that creatine may promote different responses
even in species closely related. These findings suggest
that caution should be exercised in any extrapolation from
animal data to humans in creatine investigations. Thus,
although not all of the studies had positive results, this may
have been due to their methodological approaches; creatine
supplementation, in general, was able to improve glucose
metabolism in animals experiencing insulin resistance.
Two (Souza et al. 2006; Araújo et al. 2013) out of four
animal studies (Souza et al. 2006; Freire et al. 2008; Vaisy
et al. 2011; Araújo et al. 2013) that examined the effects of
creatine supplementation combined with exercise training
on glucose metabolism demonstrated beneficial outcomes.
Freire et al. (2008) and Vaisy et al. (2011) used different
supplementation protocols than the other studies (diets sup-
plemented with 2 and 2.5 % creatine, respectively). No
influence of creatine supplementation on glucose metabo-
lism was seen in these studies (Freire et al. 2008; Vaisy
et al. 2011). Both studies had comparable intervention
periods, the animals performed similar exercise training
(swimming), and the supplementation protocol was simi-
lar, suggesting that one of the previous factors mentioned
explains the lack of glucose metabolism improvement. Pre-
vious studies (Brannon et al. 1997; McMillen et al. 2001)
that have supplemented animals with a diet containing 2 %
creatine have showed a significant increase in creatine and
phosphocreatine muscle content; however, Freire et al.
(2008) did not measure these parameters and Vaisy et al.
(2011) did not find a significant difference in these con-
tents. Therefore, it is possible that the supplementation pro-
tocol used in these studies was not able to cause changes
in the muscles and thus on glucose metabolism, despite the
fact that other studies have demonstrated that creatine sup-
plementation generates physiological adaptations (Eijnde
et al. 2001; Van Loon et al. 2004). Freire et al. (2008) also
submitted the animals to lower intensity exercise training
compared with other studies that demonstrated the altera-
tions in muscle glycogen content and, consequently, higher
rate of muscle glucose uptake (Ren et al. 1994; Nakatani
et al. 1997; Garcia-Roves et al. 2003). Another confound-
ing factor is the cafeteria diet used by Vaisy et al. (2011)
Table 3 continued
Study (year) Methods Target population nIntervention/dura-
tion of the interven-
tion
Dose Glucose metabo-
lism outcomes
Results and p
values
Relevant outcomes Results and p values
Safdar et al. (2008) Double-blind,
crossover, rand-
omized placebo-
controlled trial
Healthy, young,
non-obese men
12 Oral administration
of Cr monohy-
drate/6 weeks
Loading phase
(3 days): 20 g/day
Maintenance phase
(10 days): 5 g/day
PKB/AKT-1
expression and
protein
Between: ↑ 2.1-
fold and 4.2-fold
in Cr, respec-
tively, p < 0.05
FFM Between: ↑ 1.0 kg in
Cr, p = 0.02
MAPK expression Between: ↑
1.8-fold in Cr,
p < 0.05
Muscle total Cr
content
Between: ↑ in Cr,
p < 0.001
AKT-1 akt protein kinase B, AMPK activated protein kinase, ATP adenosine triphosphate, AUC area under the curve, BMI body mass index, C control group, Cr creatine, G group, GLUT glucose
transporter, HbA1C glycosylated hemoglobin HOMA homeostatic model assessment, HOMA-IR insulin resistance index, IR insulin receptor, MAPK p42/p44 p42/p44 mitogen-activated kinase,
mRNA messenger RNA, MTT meal tolerance test, NM not mentioned, NS not significant, OGTT oral glucose tolerance test, PCr phosphocreatine, RM repetition maximum, RNA ribonucleic acid,
S significant, VO2 maximal oxygen consumption, VO2-RCP oxygen consumption correspondent to respiratory compensation point, VO2- VAT oxygen consumption correspondent to ventilator
anaerobic threshold
a “Within”, refers to within groups comparisons
b “Between” refers to between groups comparisons

Creatine supplementation and glycemic control: a systematic review
1 3
which induced a state of glucose intolerance in addition to
muscular insulin resistance (Petry et al. 1997; Holemans
et al. 2004). Thus, the different stimuli may have gener-
ated these disparate results. The other two animal studies,
Souza et al. (2006) and Araújo et al. (2013), administered
a loading phase followed by a maintenance phase of cre-
atine supplementation over 8 weeks and submitted the
animals to high-intensity swimming or treadmill exercise,
respectively. Previous studies had already demonstrated the
efficacy of this supplementation protocol in different exer-
cise types (Brannon et al. 1997; Tarnopolsky et al. 2003;
Op’t Eijnde et al. 2001). These interventions were able to
improve glucose metabolism. Thus, depending on the sup-
plementation protocol and exercise training used, creatine
supplementation was able to improve glucose metabolism
in healthy and active animals with a potentially synergistic
effect when both interventions were used.
The last four rodent studies enrolled in this system-
atic review assessed healthy animals, and the intervention
consisted of creatine supplementation alone (Eijnde et al.
2001; Young and Young 2002; Rooney et al. 2002; Ju et al.
2005). Eijnde et al. (2001) and Young and Young (2002)
did not find a difference in glucose metabolism between the
control and supplemented groups either after 5 days of 5 g
of creatine/kg of body weight per day or after 300 mg/kg
of body weight per day over 5 weeks. Although the authors
had different supplement amounts and intervention periods,
Eijnde et al. (2001) showed increased creatine content in
slow-twitch soleus muscle and Young and Young (2002)
in fast-twitch muscle. Despite reaching different types of
muscle fibers, glucose uptake was not improved, suggest-
ing that the increase in creatine content in the muscle was
not the main factor in producing effects on glucose metabo-
lism. Although Rooney et al. (2002) found an increase in
muscle creatine content, they did not find an association
between this parameter and the improvement in glucose
metabolism after 4 and 8 weeks of treatment. Previous
studies (Alsever et al. 1970; Bolea et al. 1997; Van Loon
et al. 2000) have demonstrated that the guanidinium group
in creatine produces a structure similar to arginine, a potent
insulin secretion stimulator, which explains the altered
pancreatic insulin secretion. However, even with this
impaired insulin secretion, plasma glucose response was
not changed, reinforcing the need for studies to explain the
mechanisms, by which glucose metabolism is affected. Ju
et al. (2005) recognizing the importance of understanding
how glucose metabolism is influenced by creatine supple-
mentation at the molecular level observed that 3 weeks of
intervention led to an increase in creatine supplementation-
induced GLUT4 expression in the skeletal muscle of rats.
Nevertheless, biochemical parameters, such as plasma glu-
cose and insulin levels, were not measured.
Human studies
Stacey 1933 tested the effect of creatine ingestion on glu-
cose concentrations in humans. Since then, only a few
well-designed studies have evaluated the effects of creatine
on glucose metabolism in humans (Op’t Eijnde et al. 2001;
Fig. 2 Main action mechanisms of creatine on glucose homeostasis.
Three mechanisms are described: creatine supplementation leads to
1 GLUT translocation to the membrane to use glucose as an energy
source, thus reducing the blood glycemia; 2 AMPK stimulation, an
energy sensor that induces the modulation of glucose and fatty acids
oxidation; and 3 a probable effect on insulin’s secreting capacity that
increases the blood insulin concentrations that can bind to insulin
receptor (IR), which stimulates the insulin receptor substrate (IRS)
and activates Akt, leading to GLUT translocation to the plasmatic
membrane and attenuation of blood glycemia; 4 maximize exercise
performance (ergogenic effect) on GLUT and AMPK, improving
insulin sensitivity

C. L. Pinto et al.
1 3
Newman et al. 2003; Derave et al. 2003; Van Loon et al.
2004; Safdar et al. 2008; Gualano et al. 2008, 2011; Alves
et al. 2012), as shown in Table 3. All of the trials were pla-
cebo-controlled, 1 was single-blind (Newman et al. 2003),
7 were double-blind (Op’t Eijnde et al. 2001; Derave et al.
2003; Van Loon et al. 2004; Safdar et al. 2008; Gualano
et al. 2008, 2011; Alves et al. 2012), and 7 were rand-
omized (Op’t Eijnde et al. 2001; Newman et al. 2003; Van
Loon et al. 2004; Safdar et al. 2008; Gualano et al. 2008,
2011; Alves et al. 2012). One trial that enrolled vegetarian
individuals was excluded, because this specific population
has lower total muscle creatine content and an increased
capacity to load creatine into muscle after supplementation,
which would lead to a limitation of this review (Watt et al.
2004). Six trials investigated the effects of creatine supple-
mentation in healthy participants (Op’t Eijnde et al. 2001;
Newman et al. 2003; Derave et al. 2003; Van Loon et al.
2004; Safdar et al. 2008; Gualano et al. 2008) and two in
T2DM patients (Gualano et al. 2011; Alves et al. 2012). Six
studies (Op’t Eijnde et al. 2001; Newman et al. 2003; Der-
ave et al. 2003; Van Loon et al. 2004; Safdar et al. 2008;
Gualano et al. 2008) used a creatine supplementation load-
ing phase followed by a maintenance phase, and two stud-
ies maintained the same low dosage for the entire experi-
ment (Gualano et al. 2011; Alves et al. 2012). Five trials
tested only creatine (Op’t Eijnde et al. 2001; Safdar et al.
2008; Gualano et al. 2008, 2011; Alves et al. 2012), 2 tri-
als tested creatine plus glucose (Newman et al. 2003; Van
Loon et al. 2004), and 1 creatine and/or protein and amino
acids (Derave et al. 2003). Some trials included moderate
intensity aerobic training combined with strengthening
exercises (Gualano et al. 2008, 2011; Alves et al. 2012) or
a rehabilitation program after immobilization (Op’t Eijnde
et al. 2001; Derave et al. 2003).
The studies that did not submit the participants to exer-
cise failed to improve glucose tolerance and insulin sen-
sitivity based on the oral glucose tolerance test (OGTT)
(Newman et al. 2003) and fasting glucose and insulin con-
centrations (Van Loon et al. 2004), despite an increased
muscle creatine content. Although creatine supplementa-
tion alone increased muscle glycogen storage by 18 %,
the muscle GLUT4 mRNA and/or GLUT4 protein content,
glycogen synthase-1, and glycogenin-1 mRNA expres-
sion were not affected (Van Loon et al. 2004). The authors
hypothesized that this effect may have been related to
a modest insulinotropic creatine capacity, as noted in the
experimental study conducted by Rooney et al. (2002).
Newman et al. (2003) verified that fasting plasma insulin
levels after short-term creatine supplementation tended to
increase by approximately 30 %, which was not statisti-
cally significant. The different rates of insulin secretion in
the trials may be explained by differences in the dosage and
duration of the interventions.
Studies on creatine supplementation and exercise train-
ing in healthy individuals found additional effects on glu-
cose metabolism outcomes when compared with creatine
supplementation alone. In fact, the absence of exercise may
explain the null effects of creatine in the studies mentioned
above (Newman et al. 2003; Van Loon et al. 2004). When
creatine supplementation was combined with exercise
training and carbohydrate intake, muscle creatine storage
increased and urinary creatine loss decreased (Devries and
Phillips 2014). Creatine supplementation attenuated the
reduction of GLUT4 protein during muscle disuse (Op’t
Eijnde et al. 2001) and increased muscle GLUT4 content to
higher than baseline levels during subsequent rehabilitation
(Op’t Eijnde et al. 2001; Derave et al. 2003). Moreover, the
area under the glucose curve from the oral glucose toler-
ance test (OGTT) decreased at the end of the re-training
(Derave et al. 2003) and training periods (Gualano et al.
2008) in groups supplemented with creatine plus protein
or creatine only. This could be related to either improved
pancreatic insulin secretion or to increased peripheral insu-
lin sensitivity. Researchers have suggested that this effect
is more likely due to improved peripheral insulin sensi-
tivity rather than to facilitated insulin secretion (Derave
et al. 2003; Gualano et al. 2008). One reason is that it is
unlikely that the improved glucose tolerance in the creatine
plus protein group was caused by the elevation of GLUT4
expression in the experimental leg, because the trained
knee extensor muscle group represents only a small part of
the total muscle mass and GLUT4 expression was not aug-
mented in the contralateral control leg. There is substan-
tial evidence to indicate that changes in insulin sensitiv-
ity can occur independently of changes in skeletal muscle
GLUT4 expression (Pedersen et al. 1990). Muscle GLUT4
seems to be associated with total muscle creatine content.
After immobilization, Op’t Eijnde et al. (2001) showed an
increase of 13 % (p < 0.05) in total muscle creatine, which
was accompanied by a trend in increasing muscle GLUT4
protein (9 %, not statistically significant). In contrast, Der-
ave et al. (2003) did not observe changes in total muscle
creatine content and muscle GLUT4 protein content after
immobilization. Differences in the total muscle creatine
may be associated with the amount of creatine supple-
mented, which was higher in the studies conducted by Op’t
Eijnde et al. (2001) and Gualano et al. (2008).
Some studies have suggested that a creatine-mediated
increase in muscle GLUT4 protein was associated with
increased 5′ adenosine monophosphate-activated protein
kinase (AMPK) activity and a decreased phosphocreatine
to creatine ratio (Ponticos et al. 1998; Ceddia and Sweeney
2004). However, in both trials (Op’t Eijnde et al. 2001;
Derave et al. 2003) and in creatine and placebo groups,
the phosphocreatine to creatine ratio decreased propor-
tionately during immobilization and remained below the

Creatine supplementation and glycemic control: a systematic review
1 3
baseline value during the subsequent rehabilitation period.
Thus, evidence of a possible creatine-induced enhancement
of AMPK activity was not found in these human studies.
Op’t Eijnde et al. (2001) speculated that cellular hydration
promoted by creatine supplementation acted as an anabolic
proliferative signal, activating the mitogen-activated pro-
tein kinase (MAPK) signaling cascade. This cascade plays
a pivotal role in muscle protein synthesis regulation, which
may be involved in GLUT4 synthesis regulation and deg-
radation in muscle cells. Therefore, the increased levels of
muscle GLUT4 protein may lead to elevated muscle gly-
cogen content (Op’t Eijnde et al. 2001; Derave et al. 2003)
and an improvement in postprandial glucose profile (Der-
ave et al. 2003; Gualano et al. 2008). These results corrobo-
rated with Safdar et al. (2008) which observed an increase
protein kinase B (PKBa/Akt1) and p38MAPK pathway.
Two double-blind, randomized placebo-controlled trials
examined the effects of creatine in patients diagnosed with
T2DM (Gualano et al. 2011; Alves et al. 2012). In both
studies, creatine and placebo groups underwent a moder-
ate intensity aerobic training combined with strengthening
exercises. Creatine supplementation decreased HbA1c, the
area under the glucose curve, and glycemia at 0, 30, and
60 min, respectively, of a meal tolerance test, and increased
GLUT4 translocation (but not total GLUT4 content) when
compared to placebo (Gualano et al. 2011). Therefore, cre-
atine supplementation increased muscle GLUT4 content in
healthy individuals (Derave et al. 2003; Op’t Eijnde et al.
2001) as well as GLUT4 translocation in T2DM patients
(Gualano et al. 2011), which is important in the control
of insulin resistance. Exercise training was able to resolve
impaired GLUT4 translocation in the diabetic patients.
Interestingly, this response was further enhanced by cre-
atine supplementation, suggesting that this supplement
acts directly on T2DM pathogenesis (Gualano et al. 2011).
Similarly, the creatine only group showed improved glyce-
mic control, suggesting that the addition of the supplement
might have maximized the effects of exercise on insulin
sensitivity. According to Alves and colleagues (Alves et al.
2012), the decreased HbA1c levels and increased GLUT-4
translocation were significantly associated with the
increased AMPK-α protein expression. AMPK signaling is
activated following a rise in the adenosine monophosphate
(AMP) to adenosine triphosphate (ATP) ratio within the
cell and responds by adjusting the rates of ATP-consum-
ing and ATP-generating pathways. The signaling cascades
initiated by AMPK activation exert effects on glucose and
lipid metabolism, gene expression, and protein synthe-
sis. AMPK signaling has been considered as an important
mediator of muscle contraction-induced GLUT4 transloca-
tion and a target for pharmacological interventions to treat
altered glucose homeostasis (Towler and Hardie 2007).
As previously mentioned, creatine supplementation may
potentially affect AMPK signaling by inducing a decrease
in the phosphocreatine to creatine ratio, which would rep-
resent a change in the energy state of the muscle cell (Pon-
ticos et al. 1998; Ceddia and Sweeney 2004). In human tri-
als, creatine supplementation in conjunction with exercise
training enhanced the favorable effects on glycemic control
in healthy and individuals with T2DM. In Fig. 2, we sum-
marize the main physiological and molecular mechanisms,
by which creatine supplementation positively effects glu-
cose homeostasis in both rodents and humans.
Conclusion
Based on clinical studies, creatine supplementation, par-
ticularly when combined with training, may potentially
affect glucose uptake. In addition, creatine can maximize
exercise capacity on GLUT and AMPK, improving insu-
lin sensitivity. However, there are a very limited number of
clinical interventions testing the effects of creatine supple-
mentation in glucose metabolism precluding the prescrip-
tion of this dietary supplement as part of the treatment of
conditions characterized by insulin resistance. Regarding
animal studies, the results were largely divergent confirm-
ing that species-specific responses do exist in relation to
creatine studies. Given the potential of this intervention as
an antiglycemic agent, evidenced by (scant) experimental
and clinical data, further studies are needed to better under-
stand the effects and underlying mechanism of creatine
supplementation in modulating glycemia.
Acknowledgments We would like to thank the Fundação de Amparo
à Pesquisa do Estado de Goiás (FAPEG) for the scholarship to Camila
Lemos Pinto.
Compliance with ethical standards
Conflict of interest We declare that we have no conflicts of interest.
References
Alsever RN, Georg RH, Sussman KE (1970) Stimulation of insulin
secretion by guanidinoacetic acid and other guanidine deriva-
tives. Endocrinology 86:332–336
Alves CR, Ferreira JC, de Siqueira-Filho MA, Carvalho CR, Lancha
AH Jr, Gualano B (2012) Creatine-induced glucose uptake in
type 2 diabetes: a role for AMPK-α? Amino Acids 43:1803–1807
Araújo MB, Junior RCV, Moura LP et al (2013) Influence of creatine
supplementation on indicators of glucose metabolism in skeletal
muscle of exercised rats. Motriz 19:709–716
Bolea S, Pertusa JA, Martín F, Sanchez-Andrés JV, Soria B (1997)
Regulation of pancreatic beta-cell electrical activity and insulin
release by physiological amino acid concentrations. Pflugers
Arch 433:699–704
Bouzakri K, Karlsson HK, Vestergaard H, Madsbad S, Christiansen
E, Zierath JR (2006) IRS-1 serine phosphorylation and insulin

C. L. Pinto et al.
1 3
resistance in skeletal muscle from pancreas transplant recipients.
Diabetes 55:785–791
Branch JD (2003) Effect of creatine supplementation on body compo-
sition and performance: a meta-analysis. Int J Sport Nutr Exerc
Metab 13:198–226
Brannon TA, Adams GR, Conniff CL, Baldwin KM (1997) Effects of
creatine loading and training on running performance and bio-
chemical properties of rat skeletal muscle. Med Sci Sports Exerc
29:489–495
Ceddia RB, Sweeney G (2004) Creatine supplementation increases
glucose oxidation and AMPK phosphorylation and reduces
lactate production in L6 rat skeletal muscle cells. J Physiol
555:409–421
Copps KD, White MF (2012) Regulation of insulin sensitivity by ser-
ine/threonine phosphorylation of insulin receptor substrate pro-
teins IRS1 and IRS2. Diabetologia 55:2565–2582
DeFronzo RA (2009) Banting Lecture. From the triumvirate to the
ominous octet: a new paradigm for the treatment of type 2 diabe-
tes mellitus. Diabetes 58:773–795
DeFronzo RA, Ferrannini E, Groop L et al (2015) Type 2 diabetes
mellitus. Nat Rev Dis Primers. doi:10.1038/nrdp.2015.19
Derave W, Eijnde BO, Verbessem P et al (2003) Combined creatine
and protein supplementation in conjunction with resistance train-
ing promotes muscle GLUT-4 content and glucose tolerance in
humans. J Appl Physiol 94:1910–1916
Devries MC, Phillips SM (2014) Creatine supplementation dur-
ing resistance training in older adults-a meta-analysis. Med Sci
Sports Exerc 46:1194–1203
Eijnde BO, Richter EA, Henquin JC, Kiens B, Hespel P (2001) Effect
of creatine supplementation on creatine and glycogen content in
rat skeletal muscle. Acta Physiol Scand 171:169–176
Ferrante RJ, Andreassen OA, Jenkins BG et al (2000) Neuroprotective
effects of creatine in a transgenic mouse model of Huntington’s
disease. J Neurosci 20:4389–4397
Freire TO, Gualano B, Leme MD, Polacow VO, Lancha AH Jr
(2008) Effects of creatine supplementation on glucose uptake
in rats submitted to exercise training. Rev Bras Med Esporte
14:431–435
Garcia-Roves PM, Han DH, Song Z, Jones TE, Hucker KA, Hollo-
szy JO (2003) Prevention of glycogen supercompensation pro-
longs the increase in muscle GLUT4 after exercise. Am J Physiol
Endocrinol Metab 285:E729–E736
Gualano B, Novaes RB, Artioli GG et al (2008) Effects of creatine
supplementation on glucose tolerance and insulin sensitivity in
sedentary healthy males undergoing aerobic training. Amino
Acids 34:245–250
Gualano B, Artioli GG, Poortmans JR, Lancha Junior AH (2010)
Exploring the therapeutic role of creatine supplementation.
Amino Acids 38:31–44
Gualano B, de Salles PV, Roschel H et al (2011) Creatine in type 2
diabetes: a randomized, double-blind, placebo-controlled trial.
Med Sci Sports Exerc 43:770–778
Guzun R, Timohhina N, Tepp K et al (2011) Systems bioenergetics
of creatine kinase networks: physiological roles of creatine and
phosphocreatine in regulation of cardiac cell function. Amino
Acids 40:1333–1348
Harris R (2011) Creatine in health, medicine and sport: an introduc-
tion to a meeting held at Downing College, University of Cam-
bridge, July 2010. Amino Acids 40:1267–1270
Harris RC, Söderlund K, Hultman E (1992) Elevation of creatine in
resting and exercised muscle of normal subjects by creatine sup-
plementation. Clin Sci (Lond) 83:367–374
Hiratani K, Haruta T, Tani A, Kawahara J, Usui I, Kobayashi M
(2005) Roles of mTOR and JNK in serine phosphorylation,
translocation, and degradation of IRS-1. Biochem Biophys Res
Commun 335:836–842
Holemans K, Caluwaerts S, Poston L, Van Assche FA (2004) Diet-
induced obesity in the rat: a model for gestational diabetes mel-
litus. Am J Obstet Gynecol 190:858–865
IDF (2013) International Diabetes Federation: Diabetes Atlas. https://
www.idf.org/sites/default/files/EN_6E_Atlas_Full_0.pdf.
Accessed 01 Dec 2015
Ju JS, Smith JL, Oppelt PJ, Fisher JS (2005) Creatine feeding
increases GLUT4 expression in rat skeletal muscle. Am J Phys-
iol Endocrinol Metab 288:E347–E352
Knowler WC, Barrett-Connor E, Fowler SE et al (2002) Reduction
in the incidence of type 2 diabetes with lifestyle intervention or
metformin. N Engl J Med 346:393–403
Marco J, Calle C, Hedo JA, Villanueva ML (1976) Glucagon-releas-
ing activity of guanidine compounds in mouse pancreatic islets.
FEBS Lett 64:52–54
McMillen J, Donovan CM, Messer JI, Willis WT (2001) Energetic
driving forces are maintained in resting rat skeletal muscle after
dietary creatine supplementation. J Appl Physiol 90:62–66
Nakatani A, Han DH, Hansen PA et al (1997) Effect of endurance
exercise training on muscle glycogen supercompensation in rats.
J Appl Physiol 82:711–715
Newman JE, Hargreaves M, Garnham A, Snow RJ (2003) Effect of
creatine ingestion on glucose tolerance and insulin sensitivity in
men. Med Sci Sports Exerc 35:69–74
Nicastro H, Gualano B, de Moraes WM et al (2012) Effects of creatine
supplementation on muscle wasting and glucose homeostasis in
rats treated with dexamethasone. Amino Acids 42:1695–1701
Op’t Eijnde B, Ursø B, Richter EA, Greenhaff PL, Hespel P (2001)
Effect of oral creatine supplementation on human muscle
GLUT4 protein content after immobilization. Diabetes 50:18–23
Op’t Eijnde B, Jijakli H, Hespel P, Malaisse WJ (2006) Creatine sup-
plementation increases soleus muscle creatine content and low-
ers the insulinogenic index in an animal model of inherited type
2 diabetes. Int J Mol Med 2006(17):1077–1084
Pan XR, Li GW, Hu YH et al (1997) Effects of diet and exercise in
preventing NIDDM in people with impaired glucose toler-
ance. The Da Qing IGT and Diabetes Study. Diabetes Care
20:537–544
Pedersen O, Bak JF, Andersen PH et al (1990) Evidence against
altered expression of GLUT1 or GLUT4 in skeletal muscle of
patients with obesity or NIDDM. Diabetes 39:865–870
Petry CJ, Ozanne SE, Wang CL, Hales CN (1997) Early protein
restriction and obesity independently induce hypertension in
1-year-old rats. Clin Sci 93:147–152
Pinto CL, Botelho PB, Carneiro JA, Mota JF (2016) Impact of cre-
atine supplementation in combination with resistance train-
ing on lean mass in the elderly. J Cachexia Sarcopenia Muscle.
doi:10.1002/jcsm.12094
Ponticos M, Lu QL, Morgan JE, Hardie DG, Partridge TA, Carling
D (1998) Dual regulation of the AMP-activated protein kinase
provides a novel mechanism for the control of creatine kinase in
skeletal muscle. EMBO J 17:1688–1699
Ramachandran A, Snehalatha C, Mary S et al (2006) The Indian
Diabetes Prevention Programme shows that lifestyle modifica-
tion and metformin prevent type 2 diabetes in Asian Indian sub-
jects with impaired glucose tolerance (IDPP-1). Diabetologia
49:289–297
Ren JM, Semenkovich CF, Gulve EA, Gao J, Holloszy JO (1994)
Exercise induces rapid increases in GLUT4 expression, glucose
transport capacity, and insulin-stimulated glycogen storage in
muscle. J Biol Chem 269:14396–14401
Rooney K, Bryson J, Phuyal J, Denyer G, Caterson I, Thompson C
(2002) Creatine supplementation alters insulin secretion and glu-
cose homeostasis in vivo. Metabolism 51:518–522
Safdar A, Yardley NJ, Snow R, Melov S, Tarnopolsky MA (2008)
Global and targeted gene expression and protein content in

Creatine supplementation and glycemic control: a systematic review
1 3
skeletal muscle of young men following short-term creatine
monohydrate supplementation. Physiol Genomics 32:219–228
Souza RA, Santos RM, Osório RAL et al (2006) Influence of the short
and long term supplementation of creatine on the plasmatic con-
centrations of glucose and lactate in Wistar rats. Rev Bras Med
Esporte 12:361–365
Stacey RS (1933) The effect on the blood-sugar and blood-phosphate
of ingested creatine. Biochem J 27:690–692
Tarnopolsky MA, Bourgeois JM, Snow R et al (2003) Histological
assessment of intermediate- and long-term creatine monohydrate
supplementation in mice and rats. Am J Physiol Regul Integr
Comp Physiol 285:R762–R769
Towler MC, Hardie DG (2007) AMP-activated protein kinase in meta-
bolic control and insulin signaling. Circ Res 100:328–341
Vaisy M, Szlufcik K, De Bock K et al (2011) Exercise-induced,
but not creatine-induced, decrease in intramyocellular lipid
content improves insulin sensitivity in rats. J Nutr Biochem
22:1178–1185
Van Loon LJ, Saris WH, Verhagen H, Wagenmakers AJ (2000) Plasma
insulin responses after ingestion of different amino acid or pro-
tein mixtures with carbohydrate. Am J Clin Nutr 72:96–105
Van Loon LJ, Murphy R, Oosterlaar AM et al (2004) Creatine sup-
plementation increases glycogen storage but not GLUT-4 expres-
sion in human skeletal muscle. Clin Sci 106:99–106
Wallimann T, Tokarska-Schlattner M, Schlattner U (2011) The cre-
atine kinase system and pleiotropic effects of creatine. Amino
Acids 40:1271–1296
Watt KK, Garnham AP, Snow RJ (2004) Skeletal muscle total creatine
content and creatine transporter gene expression in vegetarians
prior to and following creatine supplementation. Int J Sport Nutr
Exerc Metab 14:517–531
Wyss M, Kaddurah-Daouk R (2000) Creatine and creatinine metabo-
lism. Physiol Rev 80:1107–1213
Young JC, Young RE (2002) The effect of creatine supplementation
on glucose uptake in rat skeletal muscle. Life Sci 71:1731–1737