Clinical Nutrition 40 (2021) 4595e4605

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Clinical Nutrition
journal homepage: http://www.elsevier.com/locate/clnu

Meta-analyses

Effects of melatonin supplementation on diabetes: A systematic

review and meta-analysis of randomized clinical trials
Felipe Mendes Delpino a, b, *, Lílian Munhoz Figueiredo b, Bruno Pereira Nunes a, b
a
Postgraduate Program in Nursing, Federal University of Pelotas, Rio Grande do Sul, Brazil
b
Faculty of Nursing, Federal University of Pelotas, Brazil

a r t i c l e i n f o s u m m a r y

Article history: Background & aims: Melatonin appears as a supplement capable of helping with diabetes. However,
Received 24 March 2021 there is no evidence from meta-analyses that showed significant results in insulin resistance and gly-
Accepted 3 June 2021 cated hemoglobin. This study aimed to review the literature on randomized clinical trials that evaluated
melatonin supplementation effects, compared to placebo, on diabetes parameters in humans. Methods:
Keywords: We conducted a systematic review and meta-analysis in the following databases: Pubmed, LILACS, Scielo,
Melatonin
Scopus, Web of Science, Cochrane, and Embase. We included randomized clinical trials investigating
Diabetes
melatonin supplementation's effects, compared to placebo, on fasting blood glucose, insulin resistance,
Glycated hemoglobin
Fasting blood glucose
and glycated hemoglobin. Non-randomized clinical trials, observation studies, and animal models were
Insulin resistance excluded. The Cochrane scale assessed the quality of the studies. We conducted a meta-analysis on
fasting blood glucose, insulin resistance, and glycated hemoglobin. Results: Sixteen studies were
included, of which 56% showed benefits from supplementation with melatonin in diabetes parameters
compared with placebo. Our meta-analysis showed significant results for fasting blood glucose [mean
difference:
4.65; 95% CI:
8.06,
1.23; p ¼ < 0.01; I2 ¼ 58%], glycated hemoglobin [mean
difference:
0.38; 95% CI:
0.67,
0.10; p ¼ 0.30; I2 ¼ 18%], and insulin resistance [mean
difference:
0.58; 95% CI:
1.00,
0.15; p ¼ 0.17; I2 ¼ 35%]. Conclusions: Our results showed that
melatonin supplementation was useful for reducing diabetes parameters when compared to placebo.
© 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

1. Introduction individuals may seek alternative treatments. In this context, com-

Diabetes is a chronic disease responsible for worsening the
quality of life and leading to more diseases. In 2019, the global
prevalence of diabetes was estimated at 9.3%, with an estimated
increase to more than 10% by 2030 [1]. Prevalence is higher in the
urban area. It is estimated that one in two people do not aware they
have the disease [1]. Deaths reported from diabetes are estimated
to increase 38% in 2030 [2]. Furthermore, there is an estimated
increase of more than 53% in costs to treat diabetes in the next two
years in America [2]. The treatment of diabetes consists of lifestyle
changes and drugs. However, drug treatment may be responsible
for undesirable side effects, such as gastrointestinal discomfort,
anorexia, nausea, abdominal discomfort, diarrhea, and reduction in
the absorption of vitamin B12 [3]. For this reason, diabetes
* Corresponding author. Department of Nursing in Public Health, Federal Uni-
versity of Pelotas, Gomes Carneiro, 01, Pelotas, RS, Brazil.
E-mail address: fmdsocial@outlook.com (F.M. Delpino).
plementary treatment with melatonin may be a viable option since
low melatonin secretion is associated with an increased risk of
developing type 2 diabetes [4].
Melatonin is a hormone responsible for regulating circadian
rhythm. Its supplementation is widely used to regulate the quality
of sleep [5]. Melatonin's physiological effects include detoxification
of free radicals and antioxidant actions, bone development and
protection, reproduction, and cardiovascular, immune, or body
mass regulation [6]. There is also evidence of protective effects of
melatonin, especially on the brain, gastrointestinal protection,
psychiatric and cardiovascular disorders [6].
In rats, a study showed that melatonin supplementation, com-
bined with exercise, may improve insulin resistance, in addition to
possibly improving antioxidant activities, hyperlipidemia, and in-
flammatory cytokines through the regulation of GLUT4, PGC-1, and
biogenesis [7]. A study in obese rats showed that melatonin sup-
plementation improved insulin sensitivity without depending on
weight loss [8]. Evidence has shown that melatonin can contribute
to the treatment of diabetes by inducing insulin secretion and

https://doi.org/10.1016/j.clnu.2021.06.007
0261-5614/© 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
F.M. Delpino, L.M. Figueiredo and B.P. Nunes Clinical Nutrition 40 (2021) 4595e4605

improving b-cells [9]. In humans, a meta-analysis showed benefits Table 1

from melatonin supplementation in fasting blood glucose. How- PICOS criteria for inclusion and exclusion of studies.

ever, the meta-analysis for insulin resistance and glycated hemo- Inclusion criteria Exclusion criteria
globin included only three and two studies in each analysis, and the Participants Studies with diabetic or Studies that were not with
results were not significant [10]. Since the last meta-analysis, there non-diabetic individuals humans
have been reports from at least seven studies that have evaluated Intervention Any melatonin Studies without melatonin
the effects of melatonin on insulin resistance and glycated hemo- supplementation dose supplementation
Comparison Placebo or usual care; any None
globin [11e17]. Therefore, a new meta-analysis could be necessary
other nonpharmacological
to provide an up-to-date evaluation of the melatonin supplemen- interventions or
tation effects on insulin resistance and glycated hemoglobin. pharmacological
Considering the lack of evidence on melatonin in parameters interventions
Outcomes Diabetes parameters: Studies that did not
such as insulin resistance and glycated hemoglobin and the
fasting blood glucose, evaluate diabetes
expressive number of new studies, this study aimed to review the insulin resistance, and parameters
literature on randomized clinical trials that evaluated the effects of glycated hemoglobin
melatonin supplementation, compared to placebo, on diabetes Study type Randomized clinical trials Observational design
parameters in humans. studies, studies that were
not carried out on humans,
and clinical trials that were
2. Methods not randomized (without
control group)
This study is a systematic review and meta-analysis about Language No limit
supplementation effects with melatonin and diabetes in humans. Year of publication No limit

We followed the recommendations of the Preferred Reporting

Items for Systematic Reviews and Meta-analyzes (PRISMA) [18].
and disagreements were solved by consensus. The scale items refer
Moreover, it was prospectively registered in the International
to questions about 1- random sequence generation (selection bias);
Prospective Registry for Systematic Reviews (PROSPERO)
2- allocation concealment (selection bias); 3- blinding of patients
(CRD42021239122).
and personnel (performance bias); 4- blinding of outcome assess-
ment (detection bias); 5- incomplete outcome data (attrition bias);
2.1. Inclusion criteria
6- selective reporting (reporting bias); 7- other bias, (other po-
tential bias, not included in the domains described above). For the
This review includes studies that evaluated the effects of sup-
last, we decided to evaluate the supplementation of other sub-
plementation with melatonin, compared to placebo, on parameters
stances in addition to melatonin. Thus, we classified as high-risk
of diabetes in individuals with or without diabetes.
studies that administered a combined supplementation using
melatonin when it was impossible to detect specific results from
2.2. Exclusion criteria
melatonin. We utilized the Review Manager 5.4 software to
perform the Cochrane scale. For analyses with more than ten
Observational studies, those with animal or in vitro, and non-
studies, we also used a funnel plot and Egger's regression tests to
randomized clinical trials were excluded.
determine publication bias, utilizing the package meta version
4.17e0 on R language [20].
2.3. Search strategy

To determine the article's eligibility, we utilized the PICOS 2.6. Meta-analysis

strategy (Population, Intervention, Comparison, Outcomes, Study
design) (Table 1). We performed the searches in the following da-
tabases (Pubmed, LILACS, Scielo, Scopus, Web of Science, Cochrane,
and Embase) until February 2021. No data or language restrictions
were applied. Two groups of keywords were used to find the arti-
cles through the Medical Subject Headings (MeSH). In the first
group used to search for melatonin, we used: “melatonin.” In the
second, terms for diabetes were used: “diabetes,” “diabetes melli-
tus,” “Type 2 Diabetes,” “T2DM,” “insulin resistance,” “fasting blood
glucose,” and “glycated hemoglobin.” We utilized the Boolean op-
erators “OR” and “AND” within or between groups, respectively.
2.4. Study selection
According to the inclusion and exclusion criteria established,
two reviewers (FMD and LMF) conducted tiles screening, followed
by abstracts and full texts. We solved the disagreements by
consensus. We also revised all references from included studies for
possible additional articles.
2.5. Risk of bias
We applied the Cochrane tool to assess the risk of bias [19]. Two
reviewers (FMD and LMF) independently assessed the risk of bias,
4596
In the quantitative analysis, we included studies that provided
mean with standard deviation (SD), before and after the interven-
tion, on fasting blood glucose, glycated hemoglobin, and insulin
resistance. For studies with no information, we assessed the mean
change using the following equation: SD change ¼ square root [(SD
baseline2 þ SD final2)
(2  R  SDbaseline  SDfinal)] [21]. We
utilized a Pearson correlation coefficient (R) of 0.5, considering it a
conservative measure for a predictable range of 0e1 [21]. For
studies that reported standard error (SEM), we calculated the
standard deviation using the following formula: SD ¼ SEM  square
root (n), where n is the number of subjects in each group. Results
are presented as the mean difference (MD) and 95% confidence
intervals (95% CI). The Higgins I2 statistic was calculated to estimate
the heterogeneity between studies. We considered as heteroge-
neity if I2> 50% and p-value <0.05, based on the test Q2 [22,23]. We
applied DerSimonian and Laird random-effects model to perform
the meta-analysis for MDs. Meta-analysis was performed utilizing
the R language through the package Meta version 4.17e0 [20]. The
level of significance was set at 5%. When necessary, we converted
fasting blood glucose in mmol/l to mg/dl. Glycated hemoglobin
(HbA1c) was analyzed in % and insulin resistance in Homeostatic
Model Assessment of Insulin Resistance (HOMA-IR). We applied
subgroup analyses by doses, less than 10 mg daily and greater than
F.M. Delpino, L.M. Figueiredo and B.P. Nunes
Fig. 1. Flowchart of the selection of studies presented in the review.
10 mg daily. We also conducted a sensitivity analysis excluding
studies that combined melatonin with other substances.
3. Results
3.1. Studies characteristics
Figure 1 shows the study selection flowchart. We find 499
unique articles. After reading the abstracts, a full reading of twenty-
six studies was considered. Of these, 13 met the inclusion criteria
and were included in the review. The main reasons for exclusion at
the last stage were: did not evaluate the outcome studied (n ¼ 7), it
was not randomized trial (n ¼ 2), repeated study (n ¼ 3), and
conference abstract (n ¼ 1). Reading the references resulted in
three articles, totaling 16 studies included in the present review.
Table 2 shows the main characteristics and results of the
included studies. Most studies (n ¼ 11) were published between
2016 and 2020 [11e17,24e27]. Most studies (n ¼ 10) were carried
4597
Clinical Nutrition 40 (2021) 4595e4605
out in Iran [11e13,15,16,24e28], followed by Iraq (n ¼ 2) [14,29].
The sample size ranged from 20 [17] to 100 individuals [25]. Two
studies were conducted only with women [13,14], one only with
men [17], and 13 with both genders. The melatonin doses ranged
from 3 [25,28] to 10 mg daily [13,14,16,17,24,26,29,30]. Two studies
combined melatonin with other substances [14,29]. Intervention
time ranged from four [17] to 24 weeks [30]. Four studies were
conducted with individuals with type 2 diabetes [12,26,27,29], and
the other 11 studies were conducted with healthy individuals or
individuals with other diseases, such as metabolic syndrome.
3.2. Main findings
Nine studies (56%) showed benefits from supplementation with
melatonin in diabetes parameters compared with placebo
[13,14,16,24e27,29,30]. From the four studies that investigated
diabetic individuals, three obtained significant results [26,27,29].
The two studies investigating only women showed significant
 Table 2

F.M. Delpino, L.M. Figueiredo and B.P. Nunes

Detailed description of each study included in the systematic review.

Identification Location Sample Age Duration in Study Adverse Intervention Main results
weeks design effects

Hussain et al., 2006 Iraq 46 individuals with type 2 Mean age of 49 12 Randomized double- No 3 groups: The groups that ingested
diabetes years blind 10 mg melatonin melatonin has
daily þ50 mg improvement in glycemic
zinc þ metformin control
10 mg melatonin
daily þ50 mg zinc
Placebo þ metformin
Gonciarz et al., 2012 Poland 42 individuals with Mean age of 42 24 Randomized open No 10 mg melatonin daily The group that ingested
nonalcoholic years in the or placebo melatonin had a significant
steatohepatitis intervention group reduction in fasting blood
and 41 in the glucose
control
Goyal et al., 2014 United States 39 individuals with Mean age of 63 10 Randomized double- No 8 mg melatonin daily or No differences in diabetes
metabolic syndrome years in the blind placebo parameters between
intervention group groups
and 58 in the
control
Modabbernia et al., 2014 Iran 36 individuals with Mean age of 33 8 Randomized double- No 3 mg melatonin daily or No differences in diabetes
schizophrenia years blind placebo parameters between
groups
Romo-Nava et al., 2014 Mexico 44 individuals with bipolar Mean age of 31 8 Randomized double- No 5 mg melatonin daily or No differences in diabetes
disorder or schizophrenia years in the blind placebo parameters between
intervention group groups
and 29 in the
control
4598

Agahi et al., 2017 Iran 100 individuals that were Mean age of 37 8 Randomized double- No 3 mg melatonin daily or The group that ingested
treated with the second- years blind placebo melatonin had a significant
generation antipsychotics reduction in fasting blood
for the first time glucose
Raygan et al., 2017 Iran 60 diabetic patients with Mean age of 68 12 Randomized double- No 10 mg melatonin daily Supplementation with
cardiovascular disease years in the blind or placebo (paraffin) melatonin has beneficial
intervention group effects on glycemic control
and 65 in the
control
Rezvanfar et al., 2017 Iran 66 individuals with type 2 Mean age of 52 12 Randomized double- No 6 mg of melatonin or Supplementation with
diabetes years blind placebo melatonin improved
control of diabetes
Bahrami et al., 2019 Iran 70 individuals with Mean age of 43 12 Randomized double- No 6 mg melatonin daily or No differences in diabetes
metabolic syndrome years blind placebo parameters between
groups
Farrokhian et al., 2019 Iran 70 individuals with type 2 Mean age of 58 8 Randomized triple- No 6 mg melatonin daily or No differences in diabetes
diabetes years blind placebo (cellulose) parameters between
groups

Clinical Nutrition 40 (2021) 4595e4605

Shabani et al., 2019 Iran 58 women with polycystic Mean age of 26 12 Randomized double- No 10 mg melatonin daily Melatonin administration
ovary syndrome years blind or placebo had beneficial effects on
insulin resistance
Abood et al., 2020 Iraq 35 women with metabolic Mean age of 46 12 Randomized double- No 10 mg The group that ingested
syndrome years in the blind melatonin þ metformin melatonin had better
intervention group or placebo results on fasting blood
and 48 years in the (lactose) þ metformin glucose and insulin
control resistance
Bahrami et al., 2020 Iran 45 individuals with non- Mean age of 44 12 Randomized double- No 6 mg melatonin daily or No differences in diabetes
alcoholic fatty liver disease years in the blind placebo parameters between
intervention group groups
F.M. Delpino, L.M. Figueiredo and B.P. Nunes Clinical Nutrition 40 (2021) 4595e4605

benefits from melatonin supplementation on insulin resistance and

sensitivity in the group that

effects on glycemic control

fasting blood glucose [13,14]. The only study that examined men
Melatonin administration

melatonin has beneficial

had beneficial effects on

found a worsening of insulin sensitivity in the group that ingested

Supplementation with
Worsening of insulin melatonin [17].

ingested melatonin
insulin resistance

3.3. Meta-analysis

Figure 2 shows the results from meta-analysis for fasting blood

glucose for the overall population and stratified by doses. The
analysis included 474 individuals in the intervention group and 453
10 mg melatonin daily

10 mg melatonin daily

10 mg melatonin daily

in the control group. Results showed that melatonin had a signifi-

cant positive effect on reducing fasting blood glucose compared to
placebo [MD:
4.65; 95% CI:
8.06,
1.23; p ¼ < 0.01; I2 ¼ 58%].
Subgroup analysis also showed significant results from studies that
or placebo

or placebo

or placebo

used doses below 10 mg daily [MD:
2.60; 95% CI:
5.02,
0.19;
p ¼ 0.35; I2 ¼ 10%]. The same occurred for the group with doses
from 10 or more mg daily [MD:
14.59; 95% CI:
24.54,
4.64;
p ¼ < 0.01; I2 ¼ 76%].
daytime sleepiness

Figure 3 shows the results for glycated hemoglobin, general and

Headache and

stratified by doses, from 155 individuals in the intervention group

and 155 in the control group. Compared to placebo, melatonin
supplementation showed benefits on HbA1c [MD:
0.38; 95%
CI:
0.67,
0.10; p ¼ 0.30; I2 ¼ 18%]. In the subgroup analysis, the
No

No

results for low doses were null [MD:
0.22; 95% CI:
0.46, 0.02;
p ¼ 0.58; I2 ¼ 0%]. For high doses, the results were significant
Randomized double-

Randomized double-

Randomized double-

[MD:
0.81; 95% CI:
1.35,
0.27; p ¼ 0.70; I2 ¼ 0%].

Results from melatonin supplementation on insulin resistance
(HOMA-IR) for the overall population and stratified by doses are
shown in Fig. 4. The analysis included 148 individuals in the
intervention group and 145 in the control group. Results showed
blind

blind

blind

that there was a significant reduction in insulin resistance in in-

dividuals who ingested melatonin [MD:
0.58; 95%
CI:
1.00,
0.15; p ¼ 0.17; I2 ¼ 35%]. After stratification by doses,
the results remained significant for studies with high doses
[MD:
0.61; 95% CI:
0.96,
0.25; p ¼ 0.29; I2 ¼ 20%]. It was not
12

12
4

possible to perform analysis for low doses because only one study
intervention group

intervention group

provided the necessary data.

Mean age of 64

Mean age of 25

Mean age of 66

Figure 5 shows the sensitivity analyses in which we excluded

and 38 in the

and 66 in the

and 64 in the

the studies that combined melatonin with other substances. The

years in the

years in the

results remained significant for glycated hemoglobin [MD:
0.26;

control

control

control

95% CI:
0.48,
0.03; p ¼ 0.54; I2 ¼ 0%], fasting blood glucose

years

[MD:
3.42; 95% CI:
6.18,
0.65; p ¼ 0.05; I2 ¼ 42%], and insulin
resistance [MD:
0.60; 95% CI:
1.07,
0.13; p ¼ 0.11; I2 ¼ 48%].
60 diabetic individuals in

3.4. Risk of bias

60 individuals with
Parkinson disease

20 healthy men

Results of the Cochrane scale are shown in Fig. 6. Only seven

hemodialysis

studies (44%) had all items classified as low risk of bias

[12,13,16,26,28,31,32]. Two of the 16 studies had item 7 (Other bias)
classified as high risk because authors combined melatonin with
other substances [14,29]. Item 2 (allocation concealment) had the
highest number of studies classified as unclear risk of bias with nine
studies [11,14,15,17,24,25,27,29,30]. The second item with the
Denmark

highest number of studies classified as unclear was item 1 (Random

sequence generation) with five studies [14,17,27,29,30]. All items
Iran

Iran

obtained at least one study classified as unclear or high risk of bias.

Figure 7 shows the funnel plot assessing the publication bias for
Daneshvar Kakhaki et al.,

Ostadmohammadi et al.,

effects of melatonin on fasting blood glucose. Egger's test for mel-

Kampmann et al., 2020

atonin's effects on fasting blood glucose was almost significant

(p ¼ 0.056).

4. Discussion
2020

2020

This systematic review and meta-analysis aimed to evaluate the

effects of melatonin supplementation on diabetes and on
4599
F.M. Delpino, L.M. Figueiredo and B.P. Nunes
Fig. 2. Forest plots of Melatonin supplementation's effects on fasting blood glucose total and stratified by doses (less than 10 mg and greater than 10 mg daily).
parameters such as fasting blood glucose, insulin resistance, and
glycated hemoglobin. Our results showed that most of the studies
obtained significant results from melatonin supplementation on
diabetes. In the meta-analyses, results were positive for fasting
blood glucose, insulin resistance, and glycated hemoglobin. This
study showed that the best results were in studies that used doses
of 10 g per day. The analysis with low doses of melatonin in glycated
hemoglobin was the only one that did not have significant results.
However, it may have been due to the low number of studies
included, only two. In our sensitivity analysis, we excluded studies
that used melatonin with other substances. Even so, the results
remained significant, showing that melatonin was effective in
controlling or treating diabetes. A previous meta-analysis found
benefic effects from melatonin on fasting blood glucose, but not for
4600
Clinical Nutrition 40 (2021) 4595e4605
insulin resistance and glycated hemoglobin [10]. The null results for
insulin resistance and glycated hemoglobin from the previous re-
view may be due to the low number of studies included, three and
two for each analysis. Our analysis added new evidence and
showed that melatonin effectively improved insulin sensitivity and
reduced glycated hemoglobin. Only one of the six studies with less
than ten weeks showed positive results [25], suggesting that longer
intervention time may be needed to demonstrate melatonin effects.
Among the 16 studies, only one reported minor side effects, such as
daytime sleepiness and headache. These symptoms can be overcome
by administering melatonin before bedtime, especially drowsiness [12].
One study found a worsening of insulin sensitivity in the group that
ingested melatonin [17]. However, this study analyzed only 20 men (10
supplemented with melatonin) and lasted only four weeks. A review
F.M. Delpino, L.M. Figueiredo and B.P. Nunes Clinical Nutrition 40 (2021) 4595e4605

Fig. 3. Forest plots of Melatonin supplementation's effects on glycated hemoglobin (HbA1C) total and stratified by doses (less than 10 mg and greater than 10 mg daily).

Fig. 4. Forest plots of Melatonin supplementation's effects on insulin resistance (HOMA-IR) total and stratified by doses (greater than 10 mg daily).

also showed that, in general, animal and human studies have shown
that melatonin supplementation in the short-term is safe, even in
extreme doses [33]. Mild adverse effects may occur, such as dizziness,
headache, nausea, and sleepiness [33]. Another review showed that
supplementation with melatonin generally has favorable safety [34].
However, there are some exceptions. The authors mention that most
adverse effects can be avoided or controlled by dosing according to
natural circadian rhythms [34]. A study that investigated children with
attention-deficit/hyperactivity disorder for 3.7 years showed no
adverse effects [35]. In another study, 33 patients supplemented
melatonin for 12 months, and the authors observed no side effects [36].
Furthermore, a review study concluded that there is a shortage of

4601
F.M. Delpino, L.M. Figueiredo and B.P. Nunes
Fig. 5. Forest plots from sensitivity analysis of Melatonin supplementation's effects on fasting blood glucose, glycated hemoglobin, and insulin resistance.
evidence from long-term randomized clinical trials on the safety of
using melatonin for long periods [37]. Therefore, we suggest ran-
domized clinical trials for long periods to prove the safety of melatonin.
Moreover, future studies should better describe the process of random
sequence and allocation of participants in the randomized clinical trial
since our scale showed a significant number of studies with unclear
risk in these items.
The mechanisms related to melatonin supplementation and
diabetes are complex. From experimental studies, there is evidence
that melatonin induces insulin growth factor production by
providing insulin receptor tyrosine phosphorylation, thereby
leading to the restoration of glucose intolerance and insulin resis-
tance through the disruption of the internal circadian system [9].
Also, there is evidence about the regulation of glucose metabolism
by the circadian system [38]. In rats, studies demonstrated that low
levels of melatonin in serum are linked with high insulin levels in
type 2 diabetes [38]. A review showed evidence about animal
studies suggesting that melatonin supplementation may have
beneficial effects on glucose homeostasis and body weight, sug-
gesting potential in the treatment of diabetes [9]. Moreover,
melatonin may induce insulin secretion signaling pathways and
improving b-cell function [9].
To the best of our knowledge, this is the first systematic review
and meta-analysis that showed significant results from melatonin
4602
Clinical Nutrition 40 (2021) 4595e4605
supplementation on glycated hemoglobin and insulin resistance.
This review and meta-analysis included many databases without
including limits on language or year of publication. However, some
limitations should be mentioned. We included in the meta-ana-
lysis's individuals with different diseases, such as nonalcoholic
steatohepatitis, bipolar disorder, and schizophrenia. Also, we con-
ducted the funnel plot analysis and egger test only for fasting blood
glucose because this was the only analysis with more than ten
studies. This decision was based on the Cochrane handbook's rec-
ommendations, in which it is mentioned that a minimum of ten
studies is necessary because, with few studies, the power of the test
is too low to distinguish chance from real asymmetry [39]. The
choice of a conservative R from 0.5 may overestimate the SD of
studies that did not provide it, and thus underestimating the sig-
nificance of specific results. However, we chose to use this con-
servative R based on previous recommendations [21,40]. Finally,
studies published in the gray literature were not included, such as
theses or dissertations, which can provide important results that
end up not being published [41].
In conclusion, our results showed that supplementation with
melatonin reduced fasting blood glucose, glycated hemoglobin,
and insulin resistance compared to placebo. Long-term ran-
domized clinical trials are suggested to prove the safety of
melatonin.
F.M. Delpino, L.M. Figueiredo and B.P. Nunes Clinical Nutrition 40 (2021) 4595e4605

Fig. 6. Cochrane risk of bias toll results for included studies.

4603
F.M. Delpino, L.M. Figueiredo and B.P. Nunes
Fig. 7. Funnel plot assessing the publication bias for effects of melatonin on fasting blood glucose.
Funding
None.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgements
All authors contributed to data interpretation and reviewed,
edited and approved the final manuscript. FMD received a doctoral
scholarship from the National Council for Scientific and Techno-
logical Development (CNPq) during the elaboration of the article.
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