Glycative Stress Research
Online edition : ISSN 2188-3610
Print edition : ISSN 2188-3602
Received : February 5, 2018
Accepted : March 22, 2018
Published online : June 30, 2018
doi:10.24659/gsr.5.2_75

Original article

Effect of melatonin intake on postprandial blood glucose in the breakfast
Mari Ogura 1), Fuka Okuda 1), Atsuhiko Hattori 2), Wakako Takabe 1), Masayuki Yagi 1),
Yoshikazu Yonei 1)
1) Anti-Aging Medical Research Center and Glycation Stress Research Center, Graduate School of Life and Medical Sciences,
Doshisha University, Kyoto, Japan
2) College of Liberal Arts and Sciences, Tokyo Medical and Dental University, Chiba, Japan

Abstract

Objectives: The link between sleep and life-style diseases related to glycolipid metabolism has been gaining considerable
concern. This study conducted a crossover trial to examine how nocturnal melatonin intake influenced blood glucose level
following the next breakfast.
Methods: Participants in the research were 12 healthy individuals (4 males and 8 females, with a mean age of 22.9
± 1.7). Subjects participated in two examinations with a one-week interval. In the first test, the standard test meal for
breakfast was steamed rice (200 g, 294 kcal). In the second test, 2 mg of melatonin was administered at 21: 00 before
the test day. On the following morning the standard test meal was ingested. In both tests, blood glucose level was
examined at 15, 30, 45, 60, 90, and 120 minutes after the time of intake of the standard meal to measure levels using aself-monitoring blood glucose meter. This study was conducted with the approval of an ethical review committee.
Results: Three cases were eliminated for data analysis: the area under the curve (AUC) in the second examination of theblood glucose response curve had great changes (± 50 % or greater). Among the nine participants, eight participants had
significantly lower AUC values due to the melatonin ingestion the night prior to the test day (from − 6.4 to − 31.0%). The
other participant showed an increase of 5.7 %. AUC was significantly lowered due to the melatonin ingestion ( p < 0.05).
Conclusion: It was suggested that the melatonin ingestion of the previous night improved the participant`s quality ofsleep, which improved postprandial hyperglycemia. We reported on the mechanism of the improvement of postprandial
hyperglycemia, adding some literature review.

KEY WORDS: postprandial hyperglycemia, melatonin, quality of sleep

Introduction

Glycation is a reaction of the bonding of reducing sugar
molecules, such as glucose or fructose, lipid, or alcoholderived aldehyde, to in vivo proteins without the controlling
action of an enzyme to form carbonylated proteins oradvanced glycation end products (AGEs). Aldehyde-loadinduced stress to living organisms is referred to as glycative
stress 1, 2). Glycative stress is a risk factor for physical aging
and contributes to the development of skin aging or diabetic
complications.
Up to 4 0 % of patients with diabetes, which is strongly
linked to glycative stress, have sleep disorders. Meanwhile,
sleep apnea syndrome (SAS), which is a major diseaseaccompanying the decline of sleep quality, is frequently

associated with complications of obesity or diabetes 3,4). That
is to say, there is a bi-directional correlation between sleepand carbohydrate metabolism. To reduce glycative stress,
prevention and treatments for the disorder of glycolipid
metabolism and sleep disorders must be performed
simultaneously. Prior research revealed that as for a
glycative stress marker, skin autofluorescence (AF) showing
an intensity of AGEs-derived fluorescence is affected byduration of sleep. Individuals with a shorter sleep duration
showed that, in the graphic chart of the level of skin AF byage, the AF value line showing changes by age was higher
in comparison to persons with a longer duration of sleep( Fig. 1 ) 5). In short, the persons with a shorter sleep duration
had a larger amount of AGEs accumulated in the skin, while

Contact Address: Professor Yoshikazu Yonei, MD, PhD
Anti-Aging Medical Research Center and Glycative Stress Research Center,
Graduate School of Life and Medical Sciences, Doshisha University
1-3 Tatara Miyakodani, Kyotanabe, Kyoto, 610-0394 Japan
Phone/Fax: + 81- 774 - 65 - 6394 E-mail: yyonei@mail.doshisha.ac.jp
Co-authors: Ogura M, m-ogura@po.kbu.ac.jp ; Okuda F, bmo2071@mail4.doshisha.ac.jp ;Hattori A, ahattori.las@tmd.ac.jp ; Takabe W, wtakabe@mail.doshisha.ac.jp ;Yagi M, myagi@mail.doshisha.ac.jp_ 75 _

Glycative Stress Research 2018; 5 (2): 075 - 081(c) Society for Glycative Stress Research

Melatonin and Postprandial Blood Glucose

the persons with a longer sleep duration showed reduced
glycative stress.
For this study, we focused on melatonin to influence thequality of sleep and examined melatonin for the anti-glycation
effect in vitro. Melatonin did not show activity for theformation of AGEs 6). In the AGEs/RAGE signaling, using acultured macrophage, melatonin had no effect 7). However,melatonin showed an effect in promoting the degradation of
AGEs 8).
Some treatment methods for reducing glycative stressare categorized as follows: the reduction of postprandial
hyperglycemia by food intake, the inhibition of glycation,and the enhancement of AGE degeneration and excretion.
The methods to reduce glycative stress are as follows:
to control postprandial blood glucose levels, to restrictglycation reactions, and to promote the degradation and theexcretion of AGEs. Specifically, the methods for controlling
postprandial blood glucose levels include selecting food witha low glycemic index (GI) as a staple, which mildly increases
postprandial blood glucose level, eating dietary fiber suchas vegetables first and carbohydrate later, and restricting
carbohydrates. This study examines whether melatoniningestion affects postprandial blood glucose levels.

Methods
Subjects

Participants were recruited from students related to
Department and Graduate School of Life and Medical
Sciences, Doshisha University. The inclusion criteria wasfor individuals who were healthy and over 20 years of age
and who did not meet the exclusion criteria. The exclusion
criteria was for individuals with the following: who areallergic to food or drugs, who are pregnant or lactating, who
are receiving pharmacotherapy, who have a disease during afollow-up observation, who have a diagnosis of diabetes, whoshow significant disorders of cardiopulmonary functions,who ingest medicine for the treatment of hypertension, whohave had a gastrointestinal surgery or who are suspectedof having an infectious disease. Participants were fully
informed of this study and written consent for voluntary
participation was obtained.
The participants of this study were 12 healthy
individuals (4 males and 8 females, with the mean age of
22.9 ± 1.7).

Protocol for blood glucose test

This study was conducted referring to Unified Protocolof Japanese Association established by the Study for
Glycemic Index (GI) 9, 10).
The guidelines as below were to be followed on the night
before the test day: refrain from strenuous exercise, do not eat
food after 22:00, do not overeat or overdrink, do not intake agreat amount of alcohol, and do not stay up late at night.
In cases where participants felt sick on the day before
the test day, prior to or during the test, the test was postponedor canceled.
On the day of the test, subjects measured fasting blood
glucose levels by themselves, using a self-monitoring blood
glucose meter. Measurements were performed twice, andthe mean value was employed as a measurement value.
When an error of measurement was 10 % or greater, anothermeasurement was performed as the third measurement, twodata entries that had the smaller error gap were employed
to calculate the mean value. The standard meal or the test
meal was ingested within a ten minute period and withapproximately thirty chewing cycles per mouthful of food.
Measurement of blood glucose level was conducted, fromthe start of the food ingestion, at 15 min (the second time),
30 min (the third time), 45 min (the fourth time), 60 min (thefifth time), 90 min (the sixth time) and 120 min (the seventhtime). Area under curve (AUC) was calculated using thechart of alternation in postprandial blood glucose levels.
To measure blood glucose levels, a self-monitoring blood
glucose meter (Glucocard G black blood glucose meter GT1830; Arkray, Kyoto, Japan) was employed.

2.5

Skin AF

2.0

1.5>8 hours ( n = 22 )1.0

5.1〜 7.9 hours ( n = 134)
< 5 hours ( n = 41)

0.5
10

20

30

40

50

Age (year)_ 76 _

Fig. 1. Skin AF and sleeping time.

Data are expressed as mean ± SEM.
A F, AG E - d e r ive d f l u o r e s c e n c emeasured by AGE Reader; SEM,
standard error mean. Figure is madeby using the data in Reference 5).

Glycative Stress Research

Clinical study design

This study employed 200 g of steamed rice as thestandard meal (Sato No Gohan Koshihikari Made in Niigata;
Sato Foods Co., Ltd., Niigata, Japan). On the intake of
steamed rice, 2.5 g of furikake, a dry Japanese seasoning
meant to be sprinkled on top of steamed rice (Noritama;
Marumiya Shokuhin Kogyou Co. Ltd., Suginami-ku, Tokyo,
Japan) was ingested with the rice. For melatonin, 2 mgof Melatonin Controlled- Release (Douglas Laboratories,
Pittsburgh, PA, USA) was used.
Melatonin (−): In the first test, blood glucose level wasmeasured at the intake of the standard meal.
Melatonin (+): The second test, 2 mg of melatonin wasingested at 21:00 on the day prior to the test day and theblood glucose level was measured for the intake of thestandard meal on the following morning.

Results

First, the results of blood glucose alternation (Cmax andAUC) in all the cases are shown ( Table 1 ). Three participants
with change rates of ± 50 % or greater in AUC between
the first and the second test were excluded for further
analysis. The reasons for the great changes of AUC were
not identifiable. The remaining nine participant`s changes inblood glucose levels after the ingestion of the standard meal
are shown in Table 2 and Fig. 2.
Blood glucose levels in cases with melatonin ingestion
were significantly lower at 15 and 120 minutes. In cases withingestion of melatonin, Δ blood glucose was significantly
lower at 120 min. There was no significant difference inCmax. However, AUC was lower in the cases with melatonin(p < 0.05).
There was no significant difference in the time of sleep
between cases with and without the ingestion of melatonin.

Statistical analysis

The amount of change Δ was determined by subtracting
the fasting blood glucose value from the postprandial blood
glucose value of passing time after the ingestion of the test
food. From the start of the ingestion to 120 minutes wascalculated AUC, the maximum concentration of the blood
glucose value (Cmax) and the maximum change (ΔCmax).
Results were expressed as standard errors of the mean (mean± standard error: SE). For the data analysis, cases where
AUC showed great gaps in change rate between two tests(± 50 % or greater) were eliminated. Statistical analysis ofpaired t-test was employed for comparison between the twogroups (IBM SPSS Statics24; IBM Japan, Ltd., Minato-ku,
Tokyo, Japan). Data was analyzed with a two-sided test anda 0.05 level of significance. A hazard rate less than 5 % wasconsidered to be statistically significant.

Table 1. AUC alteration in all the cases.

Melatonin (−)

Melatonin (+)%Change

16191.35617.5− 9.3

3198.82958.8− 7.54115.03851.3− 6.44630.04141.3−10.6

3488.85873.868.4

7427.57848.85.76843.85052.5− 26.23865.02665.0− 31.03177.55207.563. 98013.83731.3− 53. 44590.03506.3− 23. 64215.03567.5− 15. 4

2
3
4
5
6
7
8
9

Ethical standards

The Doshisha University Ethics Review Committee
on Research with Human Subjects was held to deliberate
the ethics and validity of this study. Under their approval(Application number: #16027 ) this clinical test was
conducted with UMIN Clinical Trials Registry (UMIN#
00002795).

ID

10
11

12

AUC, area under curve with units in mg/dL･min. Three participants (ID 5, 9,10) are excluded in the further analysis.

Table 2. Effect of melatonin on postprandial blood glucose.

Index
BG

Melatonin (−)
0 min
15 min30 min45 min60 min90 min
120 minCmax
AUC (mg/dL･min)
Sleeping time (hour)

87.4 ±

2.49

149.5 ±

4.85

105.1 ±
153.3 ±
147.4 ±
120.7 ±
116.2 ±

p value

85.4 ±

3.1

0.533

144.9 ±

5.5

0.388

3.79

100.1 ±

4.20

145.1 ±
134.7 ±

4.23

118.3 ±

6.93

106.1 ±

2.90

160.8 ±

4.0

6.4 ±

0.2

5008.5 ±Melatonin (+)

4.9
4.5
5.4
4.3

0.008
0.202
0.076
0.705
0.005

153.2 ±

3.8

0.113

6.4 ±

0.4

0.999

4356.5 ±

392.5

3.1

434.1

0.016

Data are expressed as mean ± SEM, n = 9, statistical analysis conducted by paired-t test. BG, blood glucose concentration in mg/dL. Cmax, maximum
concentration; AUC, area under curve.

_ 77 _

Melatonin and Postprandial Blood Glucose

Melatonin (-)

Melatonin (+)

80

ΔBlood glucose (mg/dL)

70
60
50
40
30
20
＊

＊

10

(n = 9)

0
0

20

40

60

80

100

120

Time (min)Fig. 2. Effect of melatonin on Δpostprandial blood glucose.

Melatonin 2 mg was orally administered the day before the test day. Postprandial blood glucose wasmeasured after intake of steamed rice (200 g). Bar indicates standard error mean. *p < 0.05, **p <0.01 by paired-t test.

Discussion

This trial with 12 healthy subjects ( 4 males and 8
females) examined the influences of melatonin ingested
the night prior to the test day on postprandial blood glucose
levels after breakfast on the following day. Steamed rice(200 g, 294 kcal) was ingested as the standard meal. Twoblood glucose tests were performed after the ingestion of
the standard meal. Three sets of data with AUC change
rates of ± 50 % or greater between the first and the second
test were excluded for data analysis. The data results of
the remaining nine cases showed that eight in nine cases
were lower in AUC (between − 6.4 % and − 31.0 %) and anelevation in AUC was recognized in one case (5.7 %). AUC
was significantly lowered due to the ingestion of melatonin( p < 0.05). Previous studies have reported that the ingestionof melatonin improved glycolipid metabolism. However,this study is the first to report that the single ingestion ofmelatonin improved the postprandial blood glucose levelon the following morning. The mechanism for how the
postprandial blood glucose level was lowered remains to be
examined in further investigations. We reported this casewith some literature reviews as below.
Sleep disorders have been an increasingly serious
concern in society today. Research has frequently reported
relations between shorter sleeping time and weight gain,
diabetes, hypertension, and glycolipid metabolism disorders.
Furthermore, erratic sleeping habits such as shift work sleep
disorder have diversified the risks for disease onset such asbreast cancer, diabetes, premature labor, miscarriage, lowbirth weight, small-for-gestational-age infants, interrupted
menstrual cycles, infertility, and ischemic heart disease 11).

Melatonin and glycolipid metabolism

Figure 3 shows the mechanism of melatonin to improveglycolipid metabolism and reduce glycative stress.
Firstly, melatonin has an antioxidative effect 12-22). Thiseffect is based on two functions of melatonin, which are a
powerful free-radical scavenger to eliminate ROS and widespectrum antioxidants (to promote activities of superoxide
dismutase [SOD] and glutathione peroxidase) 23, 24).
Secondly, melatonin promotes the degradation of
AGEs 25). In the disorder of carbohydrate metabolism ofdiabetes, the acceleration of endoplasmic reticulum (ER)stress in pancreatic beta cells reduces the secretion of
insulin 26). AGEs increase ER stress in pancreatic beta cells
and decreases the production and secretion of insulin 27).
Therefore, decreased AGEs due to the degradation induces
the reduction of ER stress, and consequently, the ability of
insulin secretion is improved.
Thirdly, melatonin reduces glycative stress via hormones.
Melatonin reduced the secretion of glucocorticoid, forexample, cortisol from the adrenal cortex. Glucocorticoid
promotes the acceleration of protein catabolism and the
gluconeogenesis, augment insulin resistance, thus inducing
hyperglycemia. Glucocorticoid activity, of which cortisol
accounts for 95 %, directly modulates lipid metabolism.
Cortisol, which is secreted due to acute stress, has an effecton the degradation of lipolysis and promotes the utilizationof carbohydrates, lipids and amino acids in mitochondria.
However, chronic excessive cortisol levels inhibit PPARγ(Peroxisome Proliferator -Activated Receptor γ ) of white
adipose tissue to induce the accumulation of lipids 28).

_ 78 _Glycative Stress Research

Fig. 3. Mechanism of melatonin actions on glycative stress.

ROS, reactive oxygen species; AGEs, advanced glycation end products; TG, triglyceride; HDL-C,
high-density lipoprotein-cholesterol.

Orexin, one type of cerebral hormone, effects theregulation of arousal. Orexin shows low levels during sleep
at night and is secreted around daybreak as well as diurnal
time (variation in orexin) 29-31). Width of orexin oscillation
decreases with aging. Orexin and blood glucose changes
bidirectionally affect each other and it is essential to maintainproper variations of orexin for the control of blood glucose
levels. Melatonin recovers the variations of orexin by reducing
the accelerated secretion of orexin during night time.
Fourthly, melatonin has an effect to improve lipid
metabolism. Animal model experiments have showed thatmelatonin administration to hyperlipidemic rats reduced
levels of TG and LDL-C and also a healthy rat increasedin HDL-C 32-34). Part of these results involved the effects
of insulin, as the administration of melatonin improved
insulin resistance. Pinealectomized rats were lacking in thesecretion of melatonin and showed the disorder of glycolipid
metabolism 35), which revealed that melatonin played an
influential role in maintaining the homeostasis for glycolipid
metabolism.
As stated, there are four actuating paths for melatonin to
reduce glycative stress, melatonin directly affects glycolipid
metabolism in most cases, partly via insulin effects. Though
the mechanism of effect on β cells of the pancreas is not
simple, melatonin reduces fasting insulin in the condition of
hyperinsulinemia such as borderline or early stages of type2 diabetes 36). In skeletal muscles, the effects of insulin areenhanced, and glucose uptake is activated 37, 38), which resultsin the decrease of HOMA-IR (homeostasis model assessmentof insulin resistance). It is assumed that the insulin resistanceis reduced. Furthermore, the secretion of insulin is decreasedin the condition of intensive oxidative stress and glycative
stress where the AGE formation increases and ER stressin pancreatic beta cells increases. In these conditions, thesecretion of insulin from β cells is partly supported bymelatonin, which has an anti-oxidative effect and an antiglycative effect (to promote AGE degradation). The reductionof the melatonin secretion is a risk factor for the onsetof type 2 diabetes 39). In addition, melatonin involves thehypertrophy and activation of brown adipose tissue 40). It isconsidered that melatonin is related to controlling not only
glycolipids but whole energy metabolism.

Relation to circadian rhythm

Circadian clocks have been widely observed in livingorganism and affect diverse life phenomenon including the
response of the endocrine system under stressful stimuli,
as previously reported 41). Secretions of hormones such as
crostini and orexin show the circadian rhythm according
to the internal clock. Disorders of the circadian rhythm forbiological processes would increasing the risk for the onset_ 79 _

Melatonin and Postprandial Blood Glucoseof diseases such as psychiatric disorder, immunopathy or thelife-style related diseases of obesity and type 2 diabetes 42).
Animal experiments indicate that food ingested late
before bed time is not consumed as nutrition to synthesize
muscle glycogen and resulted in the accumulation of fat 43).
Diurnal changes of muscle glycogen are minor in humans 44)
and a mechanism between time of the ingestion and the fat
accumulation has not been fully clarified. It was proven by
Jurgen Aschoff in the 1960s that the circadian cycle had aperiod of approximately 25 hours. At present the circadianperiod is considered to be 24 hours and 10 minutes basedon experiments where light environments are completely
controlled. The deviation from a 24-hour cycle of therotation period of the Earth is adjusted by resetting thecircadian rhythm through entraining agents such as exposure
to light and darkness, having meals, exercise, and social
activities. Above all, the most important factor is entrainmentof the natural light-dark cycle. The function of melatonin
is to transmit information concerning the light-dark cycle
to the tissues of the body. Ingestion of melatonin at bedtime
would be very effective to synchronize the human circadianrhythm with the Earth rotation rhythm especially to persons
at middle or advanced ages, who have a reduction in thevariations of melatonin secretion.

Research limitations

The number of participants in this research is small,and participants are young adults in their early twenties, whohave little variation of melatonin in comparison to the peakaged (between 12 and 14 years). Three cases in 12 had great
AUC changes (over ± 50 %) in the same person’s data andthe examination method had some inevitable dispersions.
However, it was interpreted that this study was able toindicate the importance of the role of melatonin, observing

the inhibition of blood glucose elevation on the following
morning due to the ingestion of melatonin the night prior to
the test day even without a great number of cases.

Conclusion

The crossover trial with 12 young, healthy adults was
conducted to examine the influences of the ingestion ofmelatonin on the blood glucose level the following morning.
It was suggested that the ingestion of melatonin the day prior
to the test day improved the quality of sleep, and there wasa possibility of the reduction of postprandial blood glucose
levels due to the melatonin. We reported on the mechanismof the improvement of postprandial hyperglycemia, adding
some literature review. It has been reported that melatoninhas effects to eliminate ROS, to promote the degradationof AGEs, to regulate the secretions of glucocorticoid andorexin, to improve insulin resistance and to modulate
glycolipid metabolism. This study was not inconsistent withthe mechanism in previous studies.

Conflict of Interest Statement

The authors state that the performance of this study
entailed no issues representing a conflict of interest.

Acknowledgements

This work was supported by JSPS KAKENHI Grant
Number #26350917.

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