Diabetes mellitus (DM) is a global health concern as 387 million people worldwide are afflicted with this disorder . According to World Health Organization (WHO), it is estimated that around 3.4 million people have died from the consequences of hyperglycemia. Moreover, the number of deaths is predicted to double between 2000 and 2030 . The two major types of DM are type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). T1DM is insulin-dependent diabetes which is caused by an autoimmune disease whereas T2DM is insulin-independent diabetes that is characterized by abnormally high insulin resistance. A combination of risk factors such as age, obesity, sedentary lifestyle or environment factors is thought to trigger T2DM in individuals that are genetically susceptible , . Patients suffering from T2DM are often observed to be accompanied by other complications such as diabetic neuropathy (DN), retinopathy, nephropathy and cardiovascular disease .
Hyperglycemia produces ROS through a few mechanisms such as mitochondrial dysfunction, labile glycation, glucose auto-oxidation and the intracellular polyol pathway . An increased level of glucose induces the production of advanced glycation end-products (AGEs) which leads to ROS production and the activation of inflammation signaling cascades, ultimately causing diabetic complications . In DM, AGEs production is observed to be enhanced in diabetic patients compared to healthy controls . Thus, the imbalance between levels of intracellular ROS and antioxidants is likely the cause of diabetic complications .
Melatonin, a hormone which is produced by pineal gland, has known anti-oxidant properties. Studies have shown that melatonin may be associated with DM in many different ways. Emerging evidence shows that melatonin reduces diabetic complications by ameliorating oxidative damage . Pancreatic beta (β) cells are especially susceptible to oxidative stress as they are known to produce high endogenous levels of ROS and do not express much of the anti-oxidative enzymes. Apart from serving as a ROS scavenger, melatonin may reduce diabetic complications such as DN, cardiovascular diseases and DR in many different ways . These roles of melatonin will also be discussed in this review.
The relationship of melatonin and diabetes
Melatonin signaling and insulin secretion
Melatonin secretion is maintained by the biological circadian rhythm where its production is released in the dark at night and inhibited when exposed to daylight. Synthesis of melatonin involves several steps where the amino acid, tryptophan is converted into serotonin which then undergoes acetylation by the enzyme serotonin-N-acetyltransferase (SNAT), finally being converted into melatonin by hydroxyindole-O-methyltransferase (HIOMT) . Melatonin receptors are G-protein coupled receptors (GPCR). The two main types of melatonin receptors in humans are melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2) , . Transcription levels of melatonin receptors are seemingly inversely proportional to the concentration of plasma melatonin, thus, reflecting that the regulation is probably modulated by a negative feedback mechanism , .
Insulin secretion is mediated through MT1 and MT2 . When the melatonin receptors are coupled to inhibitory G-proteins (Gi), the Gi-protein signaling cascade is activated and subsequently inhibits AC/cAMP and GC/cGMP pathways that results in cAMP reduction , . cAMP is the potentiator of insulin secretion. Therefore, when cAMP is reduced, insulin production is decreased. This is supported by a study that shows the binding of melatonin to its receptors would result in decreased plasma insulin level , . However, insulin secretion is induced by coupling to Gq/11, where phospholipase C is then activated via melatonin receptors and increases inositol triphosphate (IP3) or glucagon secretion which is stimulated by melatonin .
During day time, melatonin level is low and the secretion of insulin is elevated, whereas at night, the melatonin level is raised along with observations of decreased levels of insulin with increased glucose levels . Moreover, melatonin secretion is shown to decrease with age concurrent with increased insulin resistance . MT1 and MT2 receptors are expressed in the pancreatic tissues and islets in humans and rodents . Hence, melatonin might directly regulate the production of insulin or glucagon by acting on the pancreatic islets. Immunoprecipitation and immunoblotting results showed melatonin regulates the growth and differentiation of pancreatic cells . When pinealectomized rats were administered with melatonin, insulin production was increased in pancreatic β-cells along with a rise in the number of insulin receptors on the hepatocyte membranes . This suggests that melatonin is crucial for the production of insulin in the pancreatic cells. Suppression of melatonin secretion due to exposure to nocturnal light has been thought to be a critical risk factor of T2DM . In an in-vivo study, increased insulin secretion and larger β-cell mass in MT2 knockout mice can be observed compared to the wild-type litter mates. The results suggested that this could be due to the lack of inhibitory effect of melatonin as cAMP levels rose in MT2 knockout mice . This study suggests that MT2 plays an important role in the inhibitory effect of melatonin on insulin secretion. These results clearly depicted functional interrelationship between melatonin and insulin can be seen .
MTNR1B gene variants and diabetes
The role of the MTNR1B gene (the gene that encodes the MT2 receptor), in regulating the plasma glucose level and the pathogenesis of T2DM have been previously reported . Variants of the MTNR1B locus such as rs1387153 and rs10830963 have been associated with fasting glucose and T2DM. Specificity, MT2 acts primarily on the pancreas due to the close association of rs10830963 single-nucleotide polymorphisms (SNPs) with impaired insulin secretion .
The MTNR1B variant manifests increased glucose despite elevated insulin-to-glucagon ratio and predominates in β-cells unlike MTNR1A which is expressed in ⍺-cells. Rs10830963 carriers are observed to have defects in early-phase insulin production. Hence, this contributes to the rise of glucose plasma levels in carriers without T2DM , . Besides that, has also been learned that rs10830963 SNPs exhibits a bigger effect on a prediabetic person and a smaller effect when the person is on the transition to the diabetic state . However, it is unknown whether the increase of mRNA levels of MTNR1B would be correlated to the increase of MT2 expression levels as it is found to not be a trait of T2DM patients and not expressed increasingly in the pancreatic islets of T2DM . Nevertheless, MTNR1B mRNA levels are high in the pancreatic islets of rs10830963-variant carriers than people without . Variants affecting the receptor can either lead to gain or loss of function. MTNR1B has shown a loss-of-function phenotype according to the statistical analysis which established a solid link between the loss of MT2 receptor function and the risk of T2DM. Therefore, it increases the risk of T2DM 6 times  (Figure 1).
Melatonin and glucose homeostasis
Glucose homeostasis and secretion of insulin from pancreatic β-cells are maintained by the pineal gland . A decreased level of systemic melatonin circulating in the body and upregulated expression of mRNA in melatonin membrane receptor are observed in T2DM patients . It is assumed that this higher expression of melatonin membrane receptor mRNA is to compensate for the low melatonin in T2DM patients . Moreover, polymorphisms within the MTNR1B gene carrying the risk allele G has shown to increase the mRNA expression in the β-cells which causes the reduction of insulin secretion due to the decreased production of cAMP. Consequently, this increases the level of plasma glucose leading to T2DM . Clinical results have indicated that melatonin improves glycemic control and insufficiency of melatonin may lead to T2DM . Besides that, melatonin exerts glycemic control via reducing fasting plasma glucose (FPG) but not through increasing insulin secretion . Melatonin prevents the β-cells from being overstrained functionally in T2DM and inhibits insulin secretion from the β-cells . High levels of melatonin and low plasma insulin levels can be observed in T1DM and vice versa in T2DM , . A recent study has shown that the removal of MT1 has resulted in increased glucose intolerance and insulin resistance. The daily blood glucose level rhythm was altered or affected showing increasing glucose concentrations during night time when a pinealectomy is performed to remove endogenous melatonin levels . According to a study using pinealectomized rats, glucose and glucagon levels increased while insulin levels were decreased. Glucose intolerance is markedly seen but with melatonin treatment, this condition is attenuated  (Figure 2).
Melatonin and oxidative stress
Melatonin is an antioxidant which scavenges ROS (such as hydrogen peroxide and peroxynitrite anion) and reactive nitrogen species (RNS) , . It also detoxifies hydroxyl radicals and also peroxyl radicals. Moreover, it also upregulates antioxidant enzyme gene expression . According to findings of the study, melatonin increased antioxidants enzyme (glutathione, catalase, superoxide dismutase) activities in turn downregulated triglycerides, total cholesterol and low-density lipoprotein (LDL) concentration in STZ-treated diabetic rats . Oxidative stress plays an important role in the development of diabetic complications such as diabetic nephropathy, DR and cardiomyopathy.
Excessive production of ROS can lead to cellular damage of membranes, proteins, lipids and DNA . ROS are produced in mitochondria and also non-mitochondrial sites, for instance, peroxisomes . In diabetes, hyperglycemia increases levels of nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2) and inhibits the delivery of protons to complex III in the electron transport chain. This causes excessive production of ROS and leads to a buildup of oxidative stress . Influx of glucose rises intracellular glucose concentration and subsequently increases the production of superoxide anions in non-insulin dependent cells such as vascular endothelium cells .
Oxidative stress causes defective insulin signaling and impaired insulin secretion which then leads to insulin resistance and complications . According to the experiments that were carried out, additional support is contributed to melatonin being helpful for DM treatment and metabolic syndrome as melatonin may perform an anti-atherogenic effect .
Melatonin in diabetes
A decreased level of melatonin secretion is independently associated with the increased risk of type 2 diabetes developing in a patient. Hence, variant melatonin membrane receptors and low secretion of melatonin aggravate the risk of developing T2DM . A higher risk of diabetes was found to be associated with low melatonin level in women in a cohort study . A12-year longitudinal study which included 370 women with T2DM and 370 participants of matched control proved that diminished melatonin secretion level at night is independently associated with a high risk of developing T2DM .
A report has recently proved that melatonin production in the pineal gland of a streptozotocin (STZ)-induced diabetic rats is damaged due to hyperglycemia. Therefore, suggesting that deficiency of melatonin could be the representation of the hallmark of diabetic patients . Melatonin can induce secretion of insulin by the IP3 signaling pathway and also improve β-cell function. Consequently, beneficial effects can be observed on glucose homeostasis when melatonin supplement is introduced . Thus, according to a study using young Zucker diabetic fatty (ZDF) rats, glycemic control in young ZDF rats can be observed to improve with melatonin treatment .
Melatonin treatment is known to lower fasting hyperglycemia, plasma leptin, insulin and serum fatty acids. On the other hand, it is known to raise adiponectin and ameliorate insulin resistance , . Besides that, melatonin treatment used in the STZ-induced diabetes rats have demonstrated improved insulin sensitivity in their adipose tissue. However, a marked hypogonadism is shown. This could be caused by the changes in hypothalamic circuitries which are part of the reproductive control .
Melatonin in diabetic cardiomyopathy
Coronary heart disease (CHD) is one of the complications of DM . More than 80% of deaths in T2DM patients is caused by CHD. Metabolic disorders in T2DM patients may lead to inflammation and the production of free radicals which then causes vascular disorders , . Diabetic cardiomyopathy is a diabetes-associated condition which involves changes to the function and structure of myocardium . Hyperglycemia is known to activate spleen tyrosine kinase (Syk) which suppresses the activity and expression of mitochondrial complex I (COX-I). This process inevitably increases the production of cellular and/or mitochondrial ROS and triggers cardiomyocyte death through apoptosis. Studies have also demonstrated that the apoptosis of cardiomyocytes in diabetes are partially contributed by downregulation of autophagy , , . Besides that, a previous study showed that hyperglycemia induces endoplasmic reticulum (ER) stress which is a factor leading to apoptosis .
ROS promotes atherosclerosis through the expression of growth factors and activation of JNK stress signaling pathway. In addition, hyperglycemia leads to the accumulation of ALU-dsRNA in vascular endothelial cells and provokes ROS production. This results in a build-up of oxidative stress and endothelial cell dysfunction . Antioxidant treatment has been proved to be effective at reducing oxidative stress in diabetic cardiomyopathy . Melatonin is known to be one of the most potent antioxidants and also serves as a free radical scavenger which can be used as a treatment in cardiomyopathy , . In concordance with these studies, melatonin is proved to increase antioxidants enzyme (superoxide dismutase, catalase and glutathione peroxidase) activities via phosphorylation of vascular endothelial growth factor-A (VEGF-A) and decreases the levels of mTOR expression in STZ-induced diabetic cardiomyopathy rats , .
Hyperglycemia, insulin resistance and dyslipidemia which can be characterized as a metabolic syndrome together with hypertension and central obesity might be responsible for the development of atherosclerosis in T2DM subjects. Atherosclerosis is a main risk factor for cardiovascular diseases. Few studies have shown that the progression of insulin resistance to TD2M is correlated to the development of atherosclerosis. Patients undergoing both metabolic syndrome and DM have been observed to have worse coronary lesions and obstructions as compared to patients with metabolic syndrome without diabetes . High total cholesterol level is known to be a major risk factor for atherosclerosis that leads to cardiovascular diseases. Hyperlipidemia is especially prevalent in diabetic subjects , . In a study using Zucker diabetic rats, the administration of melatonin was shown to reduce the level of LDL-cholesterol while increasing level of HDL-cholesterol in plasma, therefore suggesting melatonin is a potential protective agent to be used for the endogenous cholesterol clearance , .
Furthermore, melatonin is shown to suppress the expression level of CD95 as well as the activities of capases-8 and 5 in rat cardiac tissue. By inhibiting the caspase pathways, apoptotic events can be prevented in cardiomyocytes , . This notion is further strengthened by other studies where melatonin was shown to be anti-apoptotic and protective against injury on cardiomyocytes , . According to a study, melatonin membrane receptors-dependent cGMP-PKGIα signaling plays an important role in reducing oxidative stress. Therefore, Nrf-2-HO-1 and MAPK signaling which serve as the downstream targets of the cGMP-PKGIα signaling, are regulated by melatonin to reduce cardiomyocytes injury. However, the study is only limited to STZ-induced T1DM rats, and the results might not be appropriate to be extrapolated to T2DM. Melatonin also helps to inhibit hyperpermeability of the aortic endothelium and therefore improves atherosclerosis , .
Mitochondrial fission has been studied to be associated with myocardial contractile dysfunction in diabetic subjects. It was observed that melatonin prevents cardiac dysfunction in diabetes via the inhibition of mitochondrial fission and this action is mediated by dynamin-related protein (Drp-a) . On the other hand, it is known that mitochondrial oxidative damage and mitochondrial dysfunction are associated with the pathogenesis of cardiac dysfunction in diabetic patients , . Reduced clearance of dysfunctional mitochondria impairs mitophagy, ultimately leading to diabetic cardiomyopathy. Melatonin has been reported to serve as a mitophagy enhancer by eliminating the accumulation of dysfunctional mitochondria, therefore restoring the quality control of the mitochondria and improving the cardiac function . The action of melatonin in modulating autophagy, reducing apoptosis and eliminating dysfunctional mitochondria were suggested to be associated with the Mst1/Sirt3 signaling pathway . In conclusion, melatonin can reduce oxidative stress, apoptotic events and preserving cardiac function.
Melatonin in diabetic retinopathy (DR)
DR is a major cause of vision loss in the working-age population. It is a microvascular complication associated with diabetes . During the hyperglycemic state, elevated oxidative stress can result in the thickening of the retinal basement which is presented as microangiopathy observed in DR. Besides that, as the retinal tissue is rich in lipids, it is particularly prone to oxidative stress , . As oxidative stress is augmented in diabetes, increased vascular leakage and permeability lead to the development of diabetic macular edema (DME) , . Oxidative stress triggers the para-inflammation process to amend the retina membrane. However, when this is not successful, it will lead to a chronic condition of low-grade inflammation . Capillary occlusion occurs as a result of a high amount of leukocytes produced during low-grade inflammation in the retina. This results in the subsequent upregulation of VEGF as an ischemic condition is induced.
Oxidative stress, inflammation and autophagy are known to be part of the pathogenesis of DR , . As discussed in the previous section, oxidative stress damages biomolecules which leads to apoptosis and this also upregulates expression levels of VEGF and matrix metallopeptidase 9 (MMP9) , . VEGF induces vascular dilation, microaneurysm, neovascularization, disruption of the blood-retinal barrier, angiogenesis and other abnormalities related to the vessels. Thiobarbituric acid reactive substances (TBARS), a lipid peroxidation marker, and advanced oxidation protein products (AOPP), a protein oxidation marker, have been observed to rise in the retina of diabetic-induced rats and also in the serum of patients suffering from DR , , . Apoptosis of the retina neurons is also imparted into the pathogenesis DR as ganglion cells are dying with increased proportional of apoptotic cells . Furthermore, nitrosative stress is increased in DR where NO is augmented through iNOS upregulation, forming peroxynitrite. Through lipid peroxidation decomposition, malondialdehyde (MDA) is produced. MDA is found to double in diabetic subjects as compared to the control group in studies , , , , .
Similarly, studies conducted on diabetic Sprague-Dawley rats administered with melatonin showed that melatonin decreased oxidative stress through the PI3K/Akt-Nrf2 signaling pathway. This pathway is triggered to increase the production of other antioxidants such as gluthathione and decreased inflammation through the inhibition of the NF-KB activation cascade , . By inhibiting the NF-KB cascade, pro-inflammatory cytokines are also diminished . In the retina of the diabetic rats, glutathione and glutamate cysteine ligase (GCL) are observed to be downregulated. GCL serves as the rate-limiting enzyme of the production of glutathione but when melatonin is administered, GCL level increased via Akt phosphorylation which in turn elevated Nrf2 activity , . Subsequently, this augments the GSH level in the retina and reduces polyol pathway enzymes, of which accumulation of polyols is known to be associated with damage to the cell membranes. Melatonin delays cataract formation via decreasing cytokines such as VEGF and MMPs in DR .
Besides the fact that melatonin is a potent antioxidant which reduces ROS and NOS activity in the retina, it also stimulates the production of other antioxidants such as glutathione. Moreover, some studies have shown that melatonin has a role in the maintenance of the catalase retinal activity in diabetic rats . Thus, melatonin can delay the development of DR .
Melatonin in DN
DN is a common neurological complication of diabetic patients . DN includes peripheral, autonomic, proximal and focal neuropathy. Peripheral neuropathy is the most common DN complication and represents the major cause of foot ulceration, gait disturbance, amputation and neuropathic pain , , , .
There are a few types of peripheral nervous system damage that are associated with diabetes. The most common type is the stocking-glove neuropathy, which is caused by the damage of the nerves of the foot , . Some of the earliest symptoms are detected in the feet and structural defects to the axons and Schwann cells appeared to be the predominant characteristics . DN is a disorder led by a myriad of events such as hyperglycemia, dyslipidemia and increased insulin resistance interacting with one another. These events promote the activation of pathways such as polyol, AGEs production, protein kinase C (PKC), polymerase (PARP), poly(ADP-ribose) and hexosamine , . Besides that, insulin signaling is also lost. These metabolic alterations lead to mitochondrial dysfunction, altered gene expression and ion-current defects (diminished K-channel activity and augmented Na-channel activity) together with oxidative stress and inflammation leading to nerve damage and cell death , .
A study on diabetic rats demonstrated that oxidative stress can damage a number of brain regions . Another study using STZ-induced diabetic rat models showed a reduction of acetylcholinesterase activity and NAD level and an increase of MDA level. Neurotransmitters such as gamma-aminobutyric acid (GABA) and glutamate levels were altered in the hippocampus . However, this is reversed by melatonin treatment and NAD and MDA levels were brought back to normal levels. As oxidative stress is elevated in the hyperglycemic condition, glial reactivity is increased. Melatonin treatment reduces gliosis in some of these brain regions . A study shows melatonin reduces dopaminergic fiber degeneration in the hippocampus of the rat models , . Besides that, melatonin significantly increases Nrf2 (a potent endogenous antioxidant) and heme oxygenase-1, diminishes ethanol-induced ROS and neuroinflammation by reducing NF-κB activation , , .
Melatonin has also shown to be anti-apoptotic in the neurons of diabetic patients , . Melatonin prevents apoptosis in the neuronal cells under high glucose conditions by stimulating the PTEN-induced putative kinase 1 (PINK1) expression through the MT2/Akt/NF-kB pathway . Moreover, melatonin prevents oxidative stress-induced mitochondrial dysfunction and apoptosis in high glucose-treated Schwann cells via upregulation of the Bcl2, NF-κB, mTOR, Wnt signaling pathways . Increased insulin resistance which is a pathological condition observed in T2DM patients is thought to cause cognitive decline and worsening neuropathy. Insulin resistance causes ER stress and can be eliminated with melatonin administration which suppresses the ASK1 pathway . The reduction of electrical stimulation in the peripheral nerves in the STZ induced diabetic rats. However, after 21 days of melatonin treatment, improvement was seen in the nerve conductivity velocity , . Similarly, Seyit et al. also proved that melatonin significantly improves nerve conduction velocity in STZ-induced DN rats through somatosensory evoked potentials . Melatonin improved in nerve regeneration by promoting the proliferation of Schwann cells in an in-vivo study . Therefore, this evidence suggests that melatonin plays an important role in treating DN.
DM is one of the world’s leading cause of death which is currently affecting millions of people around the globe. Hyperglycemia in diabetes causes excessive production of ROS which then leads to a build-up of oxidative stress and induction of insulin resistance. Oxidative stress is known to be related many other diabetic complications such as DN, DR, nephropathy and cardiovascular disorders. A better treatment regimen is required to target the pathogenic pathways associated with oxidative stress to improve these diabetic conditions. Melatonin confers protection against diabetes via many different mechanisms. Melatonin plays a crucial role in glycemic control by reducing FPG. Melatonin also ameliorates insulin resistance and enhances insulin sensitivity in cells. In a nutshell, melatonin treatment can be used to improve diabetic conditions in patients and reduce the incidence of diabetic complications.
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About the article
Published Online: 2019-11-06
Author contributions: JXM and JHO wrote the manuscript, and KYN and RYK critically reviewed the manuscript. SMC formulated the entire concept and reviewed the manuscript.
Research funding: None declared.
Conflict of interest: None declared.
Informed consent: Not applicable.
Ethical approval: Not applicable.