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Original Research
A Pre-Exercise Dose of Melatonin Can Alter Substrate Use During
Exercise
CARDYL P. TRIONFANTE†1, GREGGORY R. DAVIS‡2, TYLER M. FARNEY†1,
RYAN W. MISKOWIEC†1, and ARNOLD G. NELSON‡1
1School of Kinesiology, Louisiana State University, Baton Rouge, LA, USA;
School of Kinesiology, 2University of Louisiana at Lafayette, Lafayette, LA, USA
†Denotes graduate student author, ‡Denotes professional author
ABSTRACT
International Journal of Exercise Science 10(7): 1029-1037, 2017. Notwithstanding
the lack of exercise research, several reviews have championed the use of melatonin to combat
metabolic syndrome. Therefore, this study compared substrate utilization during a 30-minute
(min) graded exercise protocol following the ingestion of either 6 mg melatonin (M) or a placebo
(P). Participants (12 women, 12 men) performed stages 1-5 of the Naughton graded exercise
protocol (6 min per stage). The protocol was repeated 4 times (2x M, 2x P) at the same time of day
with one week separating each session. Expired gases were monitored, VO2 and respiratory
exchange ratio (RER) output was provided every 30s. Total, carbohydrate (CHO), and fat energy
expenditures were obtained from the RER values using the formulae of Lusk. The VO2 at which
CHO accounted for 50% of the total caloric expenditure was calculated by a VO2: RER regression
line. Additionally, the energy derived was calculated by multiplying VO2 and the respective
energy expenditures. Then, the total, CHO, and fat energies consumed during the 30 min of
exercise were determined by calculating the area under the kJ/min: time curve using the
trapezoid rule. The final data for the two similar trials were averaged and a paired-T test was
used for statistical comparison. The average VO2 for 50% CHO usage was significantly lower
following M (0.84 ± 0.54 l·min-1) than after P (1.21 ± 0.52 l·min-1). Also, average CHO kJ for M (627
± 284) was significantly (p < 0.004) greater than P (504 ± 228), and accounted for a significantly
greater contribution of total kJ consumed (M = 68% ±15 vs. P = 61% ± 18). Ingestion of melatonin
30 min prior to an aerobic exercise bout elevates CHO use during exercise.
KEY WORDS: Carbohydrate metabolism, metabolic syndrome, cross-over point,
caloric expenditure
INTRODUCTION
Metabolic syndrome clusters several metabolic abnormalities, including central (intra-
abdominal) obesity, dyslipidemia (high cholesterol and blood lipids), hyperglycemia (high
blood glucose), insulin resistance and hypertension (10, 21, 32). The ultimate importance of
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this cluster is to identify individuals at high risk for type 2 diabetes, cardiovascular disease,
and strokes (10, 21, 32). Since metabolic syndrome is an interaction between several different
disease states, numerous causative mechanisms leading to metabolic syndrome have been
identified. The major factors identified include (but not limited to) inactivity, obesity, elevated
circulating inflammatory and/or thrombotic markers (C-reactive protein, tumor necrosis
factor-α (TNF- α), interleukin-6, and plasminogen activator inhibitor type 1), reduced anti-
inflammatory molecules (adiponectin), excessive oxidative stress (too few anti-oxidants
and/or too many reactive oxygen species), and growth hormone deficiency (10, 21, 32). In
addition, recent evidence has emerged to suggest that alterations in circadian systems and
sleep participate in the pathogenesis of the disease (24).
It is possible to prevent or delay the onset of metabolic syndrome by reducing lifestyle risk
factors through moderate weight loss and increased physical activity (10, 12, 16, 21, 27).
Several studies have shown that lifestyle changes that include exercise can significantly delay
and possibly prevent this disease (12, 21, 27). Along with exercise, some experts have
championed melatonin (8, 20, 22, 39) as a chemical that can possibly help with alleviating the
symptoms of metabolic syndrome and its related diseases. Melatonin (N-acetyl-5-
methoxytryptamine) is a hormone primarily produced by the pineal gland, but is also
synthesized in the retina, kidneys, digestive tract, and leucocytes (1, 11, 22). Over the past ten
years, melatonin has been the focus of considerable attention, albeit most of the attention is
due to its function as a sleep aid or to improve circadian rhythm. Current internet search
engine queries return numerous websites devoted to espousing the benefits of melatonin. In
addition to its faddish appearance, mounting evidence in published in peer-reviewed scientific
journals provides evidence of improving metabolic risk factors from exogenous melatonin (1,
8, 9, 16, 11, 20, 28, 38, 40). All of this research suggests that melatonin has crucial roles in
various metabolic functions in addition to its role as an anti-oxidant (11, 20, 39), anti-
inflammatory (1, 9, 16, 40), chronobiotic (4, 24), and growth hormone regulator (22, 26, 29).
Despite the numerous research studies on melatonin’s influence on the aforementioned facets
of metabolic syndrome, the influence of exogenous melatonin upon the levels of blood glucose
and lipids and their interplay with exercise have not been extensively studied, and
inconsistent data have been published concerning melatonin’s influence on substrate
utilization. For instance in animal studies, exogenous melatonin increases blood glucose in
pigeons (17), but in rats melatonin can have either no influence on plasma glucose levels (18,
19) or it can cause increases in blood glucose (25, 35). In two studies where aerobic exercise to
exhaustion was performed, muscle and liver glycogen content were significantly higher in
melatonin-treated exercised animals compared to untreated exercised animals (25, 35). Also
with acute aerobic exercise, plasma and liver lactate (18), plasma free fatty acid and plasma
beta-hydroxybutyrate were significantly reduced (3, 19, 28). Melatonin-increased lipid
utilization has also been reported in Japanese quail (41). In more germane studies, when mice
were fed melatonin along with a high-fat diet, they had better control of blood glucose levels
(37). Similarly, oral melatonin reduced fasting hyperglycemia in male Zucker diabetic fatty
(ZDF) rats (2). Thus, it remains unclear how exogenous melatonin affects blood glucose or
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blood lipids and if melatonin’s effects upon these factors have a direct effect upon metabolic
outcomes.
Similar to the animal research, the influence of exogenous melatonin on humans has not been
extensively studied, and inconsistent data have been published. For instance, Peschke et al.
(33) noted that during the night, diabetic patients have lower elevations in nighttime
melatonin levels but higher blood glucose levels. The authors interpreted these occurrences as
a possible relationship between low melatonin and hyperglycemia during sleep (33). On the
other hand, Radziuk and Pye (34) showed that the nocturnal rise in blood glucose and
endogenous glucose production seen in people with type 2 diabetes coincides with an increase
in melatonin. In addition, two studies have shown promise for the use of melatonin as a
therapeutic agent for Type 2 diabetes. In one study, Hussain et al. (15) gave melatonin and zinc
acetate, alone or in combination with metformin. They found that when compared to a
placebo, the aforementioned treatments improved fasting and postprandial glycemic control
and lowered glycosylated hemoglobin (HbA1c) concentration (15). Additionally, Garfinkel et
al. (13) found that long-term administration of prolonged-release melatonin resulted in lower
HbA1c levels. In contrast to the two aforementioned studies, Cagnacci and associates (6) found
that after ingesting melatonin, post-menopausal women had both reduced glucose usage and
reduced insulin sensitivity. Additionally, a reduction in blood glucose clearance was seen
following ingestion of melatonin (31). Changes in human exercise substrate utilization with
exogenous melatonin, however, are poorly understood with only Sanders et al. (36) reporting
that blood glucose levels during graded exercise were higher following the ingestion of
melatonin.
Thus, notwithstanding the claims of different review articles (8, 20, 39), it would appear that
exogenous melatonin usage to ameliorate metabolic syndrome is not wholly supported by
human research. Unfortunately, information about the relationship in humans between
melatonin and the most widely recommended therapeutic treatment, physical exercise, is still
lacking. Therefore, the purpose of this research study was to further the information on
melatonin by evaluating substrate utilization during graded exercise with and without
exogenous melatonin. Since exercise intensity has an influence on substrate utilization, it was
decided that the initial study would look at the carbohydrate and lipid utilization ‘crossover
point’ (i.e. the workload where carbohydrate usage exceeds 50% of the total caloric
consumption.
METHODS
Participants
Twelve males (24 ± 2.4 yrs; 176 ± 4.8 cm; 85.1 ± 17.8 kg) and twelve females (24 ± 1.1 yrs; 167 ±
7.4 cm; 63.6 ± 6.5 kg) who were enrolled in graduate Kinesiology classes at Louisiana State
University (LSU) were recruited to participate in this project. All participants were healthy,
non-smoking college students, and were not taking any medications. To be considered for this
investigation, each participant had to have engaged in a minimum of 30 min of either resistive
or endurance exercise (or both) 3 days per week for the preceding six months. The study was
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approved by the LSU institutional review board, and each subject submitted both written and
oral consent before engaging in the experiment.
Protocol
A randomized balanced crossover design was used to test the acute effects of melatonin. Each
participant was tested a total of four times after ingesting either 6 mg of melatonin (twice) or a
placebo consisting of 50 mg of methylcellulose (twice). The experimental design was double-
blind in addition to placebo controlled. One week separated each treatment, and all
measurements were made at the same time of day. Prior to each visit, the subjects were asked
to refrain from exercise for 24 h and to maintain their same dietary practices. All tests were
performed before 11 am. Prior to each test, the subjects were asked to consume their normal
breakfast one hour before their scheduled test time, and to eat that same breakfast prior to
each test. Thirty minutes following the ingestion of melatonin or placebo, the substrate
utilization tests began.
The participants reported to the laboratory one hour postprandial. One of the two treatment
pills was ingested and the subject sat quietly for 30 minutes. After the rest period, the
participants started walking on the treadmill using the Naughton protocol (30). The
participants began at stage 1, and walked for six minutes at each stage, during which
expiratory gases were collected using a Parvo Medics TrueOne 2400 metabolic cart (Sandy,
UT, USA). This continued until five stages were completed (30 min).
The expired gases obtained during the graded exercise protocol were used to calculate oxygen
consumption, carbon dioxide production, and respiratory exchange ratio (RER). To determine
the ‘crossover point’, the VO2 (l·min-1) at which CHO accounted for 50% of the energy
expended was calculated. To obtain this value, participants’ VO2 (l·min-1) values and the
percentage of CHO being used (obtained from the RER using the formulae of Lusk (23)) for
each 15s of exercise were plotted against each other (VO2 on the y-axis). A regression line was
derived for this plot and the regression formulae were used to calculate the VO2 values when
CHO use was at 50% of the total caloric expenditure.
In addition, the total calories from CHO and the relative percentage of CHO utilized during
each six minute exercise stage were determined. This was calculated by plotting the product of
VO2 (l·min-1) and the respective energy expenditure (total, and CHO kJ·min-1) for each 15s of
exercise. The area under the kJ: time curve was then calculated using the trapezoid rule (14).
The total and CHO calories utilized were obtained from the RER using the formulae of Lusk
(23).
Statistical Analysis
The dependent variables analyzed were VO2 at 50% CHO as well total energy expended, total
energy derived from CHO, and total relative energy derived from CHO (CHO * Total-1). For
both the whole test (all 5 stages) and each individual stage, the values for the two tests
performed with the same supplement were averaged and these averages were used for
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analysis. A paired T-test was used to determine if a difference existed between the melatonin
and placebo conditions’ dependent variables. The level of significance was set at p < 0.05.
RESULTS
For the ‘crossover point’, there was a significant difference (p < 0.001) between the average
VO2 (l·min-1) at which the participants achieved 50% CHO usage after P (1.21 ± 0.52 l·min-1)
compared to M (0.84 ± 0.54 l·min-1). Average CHO expended (kJ) for all five stages as well as
for the total 30 minutes are presented in Figure 1. Average CHO expenditure after melatonin
(M) ingestion for the total work period as well as for stages 2-5 were significantly (p < 0.05)
greater than after the placebo (P) ingestion. There was no significant difference in CHO
expenditure between M and P during stage 1.
Figure 1. The average CHO expenditure for the entire 30 min of work as well as for Naughton Stages 1-5 after
either placebo or melatonin ingestion. * indicates a CHO expenditure following melatonin ingestion that is
significantly greater (p < 0.05) than following placebo ingestion.
Figure 2 shows the relative contribution CHO made of the total kJ consumed. The relative
contribution CHO made of the total kJ consumed for the entire 30 min of work as well as for
stages 3-5 after melatonin (M) ingestion were significantly (p < 0.05) greater than after the
placebo (P). There was no significant difference between M and P during Stages 1 & 2.
DISCUSSION
As mentioned above, notwithstanding the promotion of exogenous ingestion of melatonin as a
treatment for metabolic syndrome (8, 20, 39), research data has not been completely
supportive. For example, resting human studies have been contraindicative, with some
researchers showing a relationship between melatonin and low blood glucose (13, 15), and
others showing melatonin to be related to higher blood glucose levels (6, 31, 34). With respect
to exercise, changes in human exercise substrate utilization with exogenous melatonin,
however, are few with only Sanders et al. (36) reporting that blood glucose levels during
0"
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1st"6"min" 2nd"6"min" 3rd"6"min" 4th"6"min" 5th"6"min" Total"30"min"
Total&Carbohydrate&used&(kj)&
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melatonin"
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graded exercise were higher following glucose ingestion. Therefore, the intent of this study
was to supply initial information concerning the effect of melatonin on substrate utilization
during graded exercise. This study showed that when physically active adults ingested
melatonin 30 min prior to aerobic exercise, the predominant reliance upon CHO (Figure 2) to
fuel the exercise occurred at a lower exercise intensity than following placebo ingestion. This
earlier switch to CHO resulted in an increase in the total amount of CHO used during the
exercise (Figure 1). Thus, it would appear that melatonin ingestion prior to exercise could
enhance the anti-metabolic syndrome actions of exercise by decreasing any overabundance of
blood glucose via increased usage.
Figure 2. The relative contribution from CHO to the total kJ consumed for the entire 30 min of work as well as for
Naughton Stages 1-5 after either placebo or melatonin ingestion. * indicates a relative contribution from CHO
following melatonin ingestion that is significantly greater (p < 0.05) than following placebo ingestion.
While an increase in the removal and usage of blood glucose is desirable, before it can be
conclusively stated that the coupling of melatonin ingestion with exercise would benefit
individuals with metabolic syndrome, one must determine why melatonin increased CHO
usage. It is well documented that increased blood glucose levels during exercise leads to
enhanced glucose usage (7), and it is likely that the increased use of CHO is due a rise in blood
glucose levels triggered by the ingestion of melatonin. As mentioned above, resting human
studies have shown melatonin to be related to higher blood glucose levels (6, 31, 34).
Moreover, long-term oral melatonin led to elevated plasma glucagon in Wistar rats, and this
effect appeared to be greater when the rats were hyperglycemic (5). Additionally, Cagnacci et
al. (6) showed that the raised blood glucose post-melatonin ingestion persisted for at least 180
min. Thus, it would appear that the increased use of glucose shown in this study was due a
melatonin-induced elevation of blood glucose concentration.
In summary, the results of this study show that when melatonin is ingested by young active
healthy individuals prior to exercise, there is an increased use of glucose as a fuel for the
exercise. Unfortunately, the melatonin-induced increased use of glucose cannot ensure that a
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1st"6"min" 2nd"6"min" 3rd"6"min" 4th"6"min" 5th"6"min" Total"30"min"
%&of&Total&energy&from&
Carbohydrate&
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placebo"
melatonin"
*
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melatonin and exercise program will result in lower blood glucose post exercise. This is
because the increased use of glucose was probably due to a melatonin-influenced rise in
overall blood glucose levels. Therefore, caution should be placed upon the increased use of
CHO during exercise as an example of melatonin benefiting individuals with metabolic
syndrome. Rather this finding may point to a negative relationship between melatonin
ingestion and metabolic syndrome. If the increased use of CHO is due to a melatonin induced
increase in blood glucose, then it would be advisable to be engaged in exercise as soon as
possible after the ingestion of the melatonin. Especially if that person is using melatonin to
combat metabolic syndrome. Considering that our investigation only included 20-30 year old
participants, future research could investigate those of middle age, poor fitness levels or those
with Type 2 Diabetes. Since high melatonin encourages greater blood glucose use, it may be
possible for those with Type 2 Diabetes to have a different response to exercise to aid in
lowering blood glucose if they were to exercise in the morning as opposed to the
evening/night. Additionally, future research investigating melatonin and blood glucose levels
could incorporate individuals such as shift workers or patients with sleep disorders/sleep
deprivation. Utilizing those types of participants may help to provide some insight on
potential mechanisms responsible for the metabolic dysregulation within these populations.
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