Glycative Stress Research
Online edition : ISSN 2188-3610
Print edition : ISSN 2188-3602
Received : November 8, 2019
Accepted : January 31, 2020
Published online : March 31, 2020
doi:10.24659/gsr.7.1_105

Review article

Melatonin and glucose metabolism.
Kazuki Watanabe 1, 2), Sayaka Katagiri 2), Atsuhiko Hattori 1)
1) Department of Biology, College of Liberal Arts and Sciences, Tokyo Medical and Dental University, Ichikawa, Chiba, Japan
2) Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

Abstract

Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone secreted from the pineal gland during the night and is
known as a synchronizer of the circadian rhythm. It is a hormone that has been present not only in vertebrates but all kindsof living organisms. Recently, several reports showed that the hormone plays very important roles such as energy metabolism
and glucose metabolism, in particular. It has been reported that in animal models of type 2 diabetes, melatonin ameliorates
glucose homeostasis by improving insulin action in muscle and adipose tissues. We demonstrated that melatonin treatment
increased glucose uptake in a dose-dependent manner in a primary culture of goldfish brain cells using insulin-free medium.
These findings suggest that nocturnal melatonin increases glucose uptake in the brain via insulin independent action. To thebest of our knowledge, this study is the first to demonstrate that nocturnal melatonin directly regulates glucose uptake in placeof insulin in a vertebrate species. In this paper, we introduce new findings concerning glucose metabolism by melatonin on
mammals, and consider a role of melatonin in aspect of the evolution of glucose metabolism.

KEY WORDS: melatonin, glucose metabolism, insulin, type 2 diabetes mellitus, diurnal rhythm

1. Melatonin Existing in Various Species ofOrganism and Its Main Actions

Melatonin (N-acetyl-5-methoxytryptamine) is a hormone,belonging to amine, and is secreted mainly from the pineal
gland during the night. It is also known that it is produced inother tissues (such as retina and skin) in vertebrates, and ispresented in various organisms such as invertebrates 1), plants 2)
and cyanobacteria 3).
The secretion of melatonin is controlled by suprachiasmatic
nucleus (SCN), which is known as the existence site of thecircadian clock and it shows circadian rhythm synchronizedwith light and dark cycle. The melatonin secreted at nighttime is the signal of the start of activities of nocturnal
animals, and it induces the rest (sleep) of diurnal animals.
The daily pattern of melatonin is recognized not only inblood but also in cerebral spinal fluid, saliva and follicle
liquid. This indicates that the signal from the circadian clock
communicates with the cells all over the body through thechanges of concentration of melatonin.

So far, the existence of melatonin receptors in many
species including vertebrates and invertebrates has beenreported. For example, in the case of mammals, melatoninreceptors are expressed in almost all organs and cells
throughout the whole body such as SCN, cerebrum, retina,
spinal cord, spleen, thymus gland, pituitary gland, adrenal
gland, kidney, liver, pancreas, small intestine, heart, skin,lung, testis, ovary, blood vessel, lymphocytes and osteoblasts( Fig. 1 ). In the case of mammals, G-protein coupledmembrane MT1 and MT2 receptors exist, and RORα andRZR, which are nuclear receptors, also are considered as
candidates for melatonin receptors. Furthermore, melatoninhas various action mechanisms such as binding with proteinsof calmodulin and quinone reductase and melatonin itself
being a free radical scavenger. It is considered that it’s
probably because melatonin is a very old substance 4) inevolutionary terms.
As the main action of melatonin, a synchronizing effectof circadian rhythm is mentioned. Recently, in addition,
its various effects have been clarified, such as its strong

Corresponding to: Prof. Atsuhiko Hattori, PhD
Department of Biology, College of Liberal Arts and Sciences,
Tokyo Medical and Dental University,
2- 8 -30 Konodai, Ichikawa, Chiba 272-0827, Japan

TEL: +81-47-300-7126 e-mail: ahattori.las@tmd.ac.jp
Co-authors: Watanabe K, kwatperi@tmd.ac.jp ; Katagiri S, kataperi@tmd.ac.jp_ 10 5 _Glycative Stress Research 2020; 7 (1) : 105- 109(c) Society for Glycative Stress Research

Melatonin and Glucose Metabolism
9Figure 1Fig. 1. Distribution of membrane receptors (MT1/MT2) in body of mammals including humans.
Membrane receptors for melatonin exist in the tissues of almost whole body.

antioxidant action 5), promotion of bone formation 6), inhibitionof bone absorption 7) and activation of the immune system 8).
Furthermore, it is reported that melatonin controls thecircadian rhythm of body temperature 9) and plays importantroles in energy metabolism.

2. Melatonin’s Effect on Glucose
Metabolism in Mammals

Recent reports suggested that melatonin ameliorates
energy metabolism, especially glucose metabolism. Actually,
since a long time ago, the relationship between melatonin
and glucose metabolism in rodents has been suggested. For
example, research in the 1960s showed that abnormal glucosetolerance and glycogen synthesis inhibition were caused bypinealectomy 10), and also recently, glucose intolerance andthe inhibition of insulin signaling in peripheral tissues (liver,adipose tissue and muscle) in pinealectomized animals arereported 11). Meanwhile, it is reported that melatonin improved
glucose metabolism and insulin resistance in animal modelsof type 2 diabetes mellitus (T2DM) 12), and it has beensuggested that melatonin contributes to the improvement of
the condition of diabetic patient. In the physiological andpathological states related to reduced melatonin levels due
to aging, shift work, and exposure to light during the night,
glucose intolerance, insulin resistance, and other alterations
associated with metabolic disorder can be seen 13). It isreported that lower melatonin secretor was associated witha higher developing T2DM 14) and several variants in MT2
associated with increased risk of type 2 diabetes 15). As
stated above, it is suggested that melatonin is possibly

involved in the diabetes of humans.
Recent studies showed that the insulin resistance andglucose intolerance induced by pinealectomy are caused by
the inhibition of intracellular transmission systems induced
by insulin. The expression of mRNA of glucose transporter
4 (GLUT4) in the insulin-sensitive tissues (fat and muscle)
on animals with lower melatonin by pinealectomy wassignificantly decreased, compared with control group, which
can be improved by treatment of melatonin 16). Meanwhile,
concerning the abnormity (lowering) of insulin signals indiabetic animal models, insulin signaling is activated througha transient increase of tyrosine phosphorylation activitiesof the insulin receptor caused by treatment of melatonin,
followed by tyrosine phosphorylation of IRS-1, and thecombination of PI3 kinase and SHP-2 17). This series ofreactions are inhibited by the antagonist or blocking agent of
the melatonin receptor. Furthermore, intracellular transportof glucose via GLUT4 can be increased, through Akt
phosphorylation caused by tyrosine phosphorylation of IRS1 and activation of PI3 kinase in adipose tissue by treatmentof melatonin 18). It suggests that inhibiting FOXO1 and PGC1
located downstream of PDK-1 and Akt affects deactivationof gene expression of gluconeogenesis. From the above, it
is suggested that melatonin promotes uptake of glucose indiabetic animal models by increasing insulin signals (Fig. 2).

3. Physiological Significance Concerning
Glucose Metabolism by Melatonin at Night

Melatonin is secreted from the pineal gland at night.
What is its physiological significance in glucose metabolism?

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10Figure 2

Fig. 2. Abnormity of insulin signal in type 2 diabetic animal models and melatonin improving it.

Signaling by melatonin is cross talking with insulin signal. “ Red ” shows the pathways promoted by melatonin and “ blue”
shows those inhibited by melatonin. (But some pathways are speculated mechanisms by the authors based on recent reports.)

In the reports on rodents and humans so far, it was clarified
that insulin levels in blood are lower at night when a larger
amount of melatonin is secreted 19, 20). Several reports showthat insulin secretion from the pancreas is inhibited bymelatonin treatment 21). Plasma insulin levels in MT2 deficient
mice increased compared with the control group. As thephysiological significance of this, it is possible that melatoninsecreted at night inhibits the secretion of insulin from β-cells
and restricts glucose uptake to peripheral tissues including
muscle and fat at night.
So far, no orthologs of mammalian GLUT4 (typicalinsulin-dependent glucose transporter) have been found inzebrafish. Recently, we obtained the following results by using
goldfish, genetically close to zebrafish. Using an insulin-free
medium, we demonstrated that melatonin treatment increased
glucose (actually 2-deoxyglucose) uptake in a primary cultureof goldfish brain cells. 2-deoxyglucose is not metabolized
by the glycolysis system after being incorporated by cells, sothat it is often used in glucose uptake experiments. GLUT2(insulin-independent glucose transporter) is expressed in thebrain of goldfish, so the possibility shows that there exists aninsulin-independent glucose uptake mechanism via GLUT2(Fig. 3). Melatonin secreted at night inhibits the secretionof insulin, it increases the uptake of glucose into the brain
through a mechanism that is not dependent with insulin, andis involved in the maintenance of brain function at night(for example memory formation). This is considered to be a
new finding concerning melatonin involvement in glucose
metabolism.

4. Melatonin’s Involvement in Energy
Metabolism in Lower Organisms

The authors consider the relationship of melatonin toenergy metabolism in living organisms from an evolutionary
perspective. Some cyanobacteria (Synechocystis sp. P C C
6803) live by taking glucose as nourishment and the structureof the membrane protein (GlcP) of its glucose transporteris greatly similar to GLUT in mammals 22), and it is also
known that it shares high homology with XylE expressed in
Escherichia coli 23). It is also known that FGT-1 (mammalianGLUT2-like facilitative glucose transporter), mainly glucose
transporter protein expressed in nematode also shares highhomology with GLUT 24). Thus, the existence of glucose
transporter is widely confirmed in animal species before
vertebrates appeared. In examining molecular evolution ofglucose transporters, they have been highly preserved inorganisms from bacteria to mammals (Fig. 4 ). Meanwhile,melatonin is a hormone (substance) that has existed for a longtime in evolutionary terms. It is very interesting if melatonin
is involved in glucose metabolism in lower organisms.
There is glucose as an energy source for vertebrates. In
order to maintain a living organism stably, a constant energy
supply is required. Highly concentrated trehalose is dissolved
in insect body fluid and mainly sucrose is delivered throughvascular bundles in plants. However, they do not always
exist as energy sources. The problem that aquatic animals
first faced when they ventured onto land was preventing
themselves from drying out. It is considered that trehalose_ 10 7 _Melatonin and Glucose Metabolism
11Figure 3Fig. 3. Physiologicalsignificance of glucose metabolism by melatonin at night.

It is reported that melatonin inhibits the secretion of insulin from β-cells of the pancreas. Meanwhile, it is also reported that theuptake of glucose in the brain significantly increases at night when the level of melatonin is high compared with that in daytime.
Melatonin treatment significantly increased glucose uptake in the primary culture of brain cells in insulin-free culture medium,so that it is considered that melatonin at night inhibits the uptake of glucose to peripheral tissues (muscle and liver) and that
increases the uptake of glucose into the brain via insulin independent action.
12Fig. 4. Molecular evolution
Figure 4 of glucose transporter.

Glucose transporter has been highly preserved from prokaryote and it exists in bacteria (Escherichia coli) and cyanobacteria(Synechocystis sp. PCC 6803). Glut2 diverged at an early stage among typical four kinds of glucose transports (1-4) in humans.

_ 10 8 _Glycative Stress Researchand sucrose, in particular, performed functions against
drying out and freezing. It is known that trehalose andsucrose are converted to glucose and, in the part of insects
and plants, they are used as energy sources 25).

Conflict of interest
The authors claim no conflict of interest in this study.

Acknowledgments

5. Conclusion
Melatonin is a very interesting hormone having variousfunctions. It is expected that melatonin’s involvement inglucose metabolism and diabetes will be clarified in greater
detail in the future.

References

This work was supported by JSPS KAKENHI Grant
Number 18K11016. This study was presented at the 11thEndocrinology Section Meeting of Japanese Society ofAnti-Aging Medicine / the 18th Meeting of Glycative StressResearch on September 1, 2019, Kyoto, Japan.

13) Karlsson B, Knutsson A, Lindahl B. Is there an association

1) Migliori ML, Romanowski A, Simonetta SH, et al. Daily

variation in melatonin synthesis and arylalkylamine
N-acetyltransferase activity in the nematode Caenorhabditis
elegans. J Pineal Res. 2012; 53: 38-46.
2) Hattori A, Migitaka H, Iigo M, et al. Identification ofmelatonin in plants and its effects on plasma melatoninlevels and binding to melatonin receptors in vertebrates.
Biochem Mol Biol Int. 1995; 35: 627-634.
3) Manchester LC, Coto-Montes A, Boga JA, et al. Melatonin:
An ancient molecule that makes oxygen metabolicallytolerable. J Pineal Res. 2015; 59: 403-419.
4) Hattori A. The distribution of Melatonin in the nature.
In: Recent Development in Melatonin Research, ed. The
Society for Melatonin Research, Seiwa Shoten Publishers,
Tokyo, 2004; pp17-33. (in Japanese)5) Reiter RJ, Tan DX, Osuna C, et al. Actions of melatonin inthe reduction of oxidative stress. A review. J Biomed Sci.
2000; 7: 444-458.
6) Satomura K, Tobiume S, Tokuyama R, et al. Melatonin
at pharmacological doses enhances human osteoblastic
differentiation in vitro and promotes mouse cortical boneformation in vivo. J Pineal Res. 2007; 42: 231-239.
7) Suzuki N, Hattori A. Melatonin suppresses osteoclastic andosteoblastic activities in the scales of goldfish. J Pineal Res.
2002; 33: 253-258.
8) Carrillo-Vico A, Lardone PJ, Alvarez-Sánchez N, et al.
Melatonin: Buffering the immune system. Int J Mol Sci.
2013; 14: 8638-8683.
9) Saarela S, Reiter RJ. Function of melatonin inthermoregulatory processes. Life Sci. 1994; 54: 295-311.
10) Milcu I, Nanu L, Marcean R, et al. The action of pineal
extract and epiphysectomy on hepatic and muscularglycogen after prolonged infusion of glucose. Stud Cercet
Endocrinol. 1963; 14: 651-655.
11) Lima FB, Machado UF, Bartol I, et al. Pinealectomy
causes glucose intolerance and decreases adipose cell
responsiveness to insulin in rats. Am J Physiol. 1998; 275:E934-E941.
12) Agil A, Rosado I, Ruiz R, et al. Melatonin improves
glucose homeostasis in young Zucker diabetic fatty rats.
J Pineal Res. 2012; 52: 203-210.

between shift work and having a metabolic syndrome?
Results from a population based study of 27,485 people.
Occup Environ Med. 2001; 58: 747-752.
14) McMullan C J, Schernhammer ES, Rimm EB, et al.
Melatonin secretion and the incidence of type 2 diabetes.
JAMA 2013; 309: 1388-1396.
15) Karamitri A, Plouffe B, Bonnefond A, et al. Type 2 diabetesassociated variants of the MT2 melatonin receptor affectdistinct modes of signaling. Sci Signal. 2018; 11: eaan6622.
16) Zanquetta MM, Seraphim PM, Sumida DH, et al. Calorie
restriction reduces pinealectomy-induced insulin resistanceby improving GLUT4 gene expression and its translocation
to the plasma membrane. J Pineal Res. 2003; 35: 141-148.
17) Ha E, Yim SV, Chung JH, et al. Melatonin stimulates glucose
transport via insulin receptor substrate-1/phosphatidylinositol
3-kinase pathway in C2C12 murine skeletal muscle cells.
J Pineal Res. 2006; 41: 67-72.
18) Jiménez-Aranda A, Fernández-Vázquez G, Campos D, etal. Melatonin induces browning of inguinal white adipose
tissue in Zucker diabetic fatty rats. J Pineal Res. 2013; 55:416-423.
19) Kalsbeek A, Strubbe JH. Circadian control of insulin
secretion is independent of the temporal distribution offeeding. Physiol Behav. 1998; 63: 553-558.
20) Boden G, Ruiz J, Urbain JL, et al. Evidence for a circadianrhythm of insulin secretion. Am J Physiol. 1996; 271:
E246-E252.
21) Tuomi T, Nagorny CLF, Singh P, et al. Increased melatoninsignaling is a risk factor for type 2 diabetes. Cell Metab.
2016; 23: 1067-1077.
22) Zhang CC, Durand MC, Jeanjean R, et al. Molecular andgenetical analysis of the fructose-glucose transport systemin the cyanobacterium Synechocystis PCC6803. Mol
Microbiol. 1989; 3: 1221-1229.
23) Sun L, Zeng X, Yan C, et al. Crystal structure of a bacterial
homologue of glucose transporters GLUT1-4. Nature.
2012; 490(7420): 361-366.
24) Feng Y, Williams BG, Koumanov F, et al. FGT-1 is themajor glucose transporter in C. elegans and is central toaging pathways. Biochem J. 2013; 456: 219-229.
25) Dus M, Min S, Keene AC, et al. Taste-independent
detection of the caloric content of sugar in Drosophila.
Proc Natl Acad Sci USA. 2011; 108: 11644-11649.

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