The role of melatonin in the onset and progression of type 3 diabetes
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Alzheimer’s disease (AD) is defined by the excessive accumulation of toxic peptides, such as beta amyloid (Aβ) plaques and intracellular neurofibrillary tangles (NFT). The risk factors associated with AD include genetic mutations, aging, insulin resistance, and oxidative stress. To date, several studies that have demonstrated an association between AD and diabetes have revealed that the common risk factors include insulin resistance, sleep disturbances, blood brain barrier (BBB) disruption, and altered glucose homeostasis. Many researchers have discovered that there are mechanisms common to both diabetes and AD. AD that results from insulin resistance in the brain is termed “type 3 diabetes”. Melatonin synthesized by the pineal gland is known to contribute to circadian rhythms, insulin resistance, protection of the BBB, and cell survival mechanisms. Here, we review the relationship between melatonin and type 3 diabetes, and suggest that melatonin might regulate the risk factors for type 3 diabetes. We suggest that melatonin is crucial for attenuating the onset of type 3 diabetes by intervening in Aβ accumulation, insulin resistance, glucose metabolism, and BBB permeability.
KeywordsMelatonin Type 3 diabetes Alzheimer’s disease (AD) Insulin resistance Hyperglycemia Blood brain barrier (BBB) Beta amyloid (Aβ)
Blood brain barrier
Central nervous system
Glucose transporter 1
Glycogen synthase kinase
Mild cognitive impairment
Melatonin receptor 1
Intracellular neurofibrillary tangles
Reactive oxygen species
Type 1 diabetes
Type 2 diabetes
tumor necrosis factor-α
Vascular endothelial growth factor
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder that is characterized by the abnormal aggregation and accumulation of toxic peptides resulting in beta amyloid (Aβ) plaques and intracellular neurofibrillary tangles (NFT) . According to recent reports, the number of patients with AD will be over 13.8 million by 2050, which will place a tremendous burden on society globally [2, 3, 4]. The onset of AD is linked to various causes, such as genetic mutations [5, 6], sex , lipid metabolism [8, 9, 10, 11], aging [12, 13, 14], and diet [9, 15]. AD pathology results from excessive oxidative stress, synaptic loss, neuronal cell death, impaired insulin signaling, and abnormal glucose metabolism [16, 17, 18]. Cohort studies have demonstrated that type 2 diabetes (T2DM) increases the risk of dementia and results from common risk factors associated with dementia, including insulin resistance and hyperglycemia . Many patients with metabolic diseases, such as cardiovascular disease, diabetes, and obesity, are reported to have a progressive decline in cognitive function, leading to the development of AD [20, 21]. One meta-analysis showed that diabetes significantly increases the risk for AD in elderly people . Owing to the common risk factors between diabetes and AD, recent studies have proposed that AD is a brain-specific type of diabetes, which they termed “type 3 diabetes” [17, 23, 24, 25].
Melatonin (N-acetyl-5-methoxytryptamine) is mainly secreted as a neurohormone by the pineal gland . It plays a role in various physiological functions, including circadian rhythm regulation, antioxidant activities, and the regulation of mitochondrial function [27, 28, 29, 30]. Given that sleep disorders frequently occur in up to 45% of patients with AD [31, 32, 33], melatonin is an important hormone for the treatment of AD since it corrects abnormal sleep patterns [34, 35]. In AD, melatonin levels are decreased in the cerebrospinal fluid (CSF) compared to those in the normal population [36, 37]. Several studies have demonstrated that melatonin reduces Aβ accumulation , tau hyperphosphorylation , synaptic dysfunction , and blood brain barrier (BBB) permeability . Moreover, melatonin attenuates insulin resistance , and regulates glucose homeostasis [43, 44]. In this review, we summarize the therapeutic functions of melatonin in type 3 diabetes from various perspectives.
The risk factors for diabetes contribute to the onset and progression of Alzheimer’s disease
Insulin resistance leads to cognitive decline
Hyperglycemia triggers BBB disruption leading to cognitive dysfunction
Melatonin in AD
Melatonin has been shown to have neuroprotective effects in a mouse model of AD [114, 115], since it attenuates Aβ accumulation and synaptic dysfunction by stabilizing the mitochondria function and inhibiting DNA damage [38, 40]. Melatonin controls several molecular signaling pathways, such as PI3/Akt/GSk3β and hemooxygenase-1 [39, 116, 117], and free radical scavenging mechanisms [118, 119] in the AD brain. A recent study demonstrated that melatonin improves synapse dysfunction via the Notch1/Hes1 signaling pathway in the hippocampus . Another study suggested that melatonin inhibits apoptotic mediators and promotes pro-survival signaling in a model of AD . An animal study demonstrated that chronic melatonin treatment for 30 days improves memory impairments in the AD mouse model . Moreover, in patients with AD, melatonin levels were significantly decreased in the serum and CSF, and levels of melatonin were considered as a candidate risk factor for diagnosis of AD [37, 122]. Clinically, melatonin and its agonist have been regarded as treatments for AD [123, 124]. As mentioned above, melatonin has the potential to attenuate AD pathology via numerous mechanisms including PI3K/Akt/GSK3β  and Notch1 signaling , and RAGE/NF-κB/JNK signaling pathway . Future study of the specific mechanisms of melatonin in the CNS is necessary to identify potential therapeutic solutions for AD.
The relationship between melatonin and type 3 diabetes
Melatonin protects cells against Aβ toxicity and inhibits tau hyperphosphorylation
Aβ, the main component of amyloid plaques, is believed to cause memory dysfunction . Melatonin improves soluble Aβ-induced memory dysfunction and synaptic dysfunction via the Musashi1/Notch1/Hes1 signaling pathway , suggesting that the modulation of Notch1 could restore neurogenesis and cognitive function in AD models . According to the results of an in vivo study, melatonin administration inhibits the expression of amyloid precursor protein-cleaving secretases in the hippocampus . In addition, melatonin attenuates the memory impairments induced by Aβ accumulation in a sporadic AD model [38, 128, 129]. Melatonin inhibits the transcription of β-secretases via the melatonin receptors in SH-SY5Y neuronal cells . Melatonin attenuates Aβ-induced memory dysfunction and tau hyperphosphorylation via the PI3/Akt/GSK3β pathway in the mouse brain . Melatonin suppresses the activity of GSK3β through activation of p-GSK3β (Ser9) in Aβ in vitro model . Moreover, it improves Aβ-induced impairments in hippocampal long-term potentiation (LTP) in rats . Melatonin inhibits superoxide anion production in microglia under conditions of Aβ toxicity . In addition, it inhibits memory dysfunction and tau phosphorylation in rats . Considering the effect of melatonin on Aβ toxicity and tau hyperphosphorylation in AD, melatonin may be a key to improving memory function by suppressing the cell damage induced by Aβ toxicity and tau hyperphosphorylation.
Melatonin protects cells against insulin resistance and hyperglycemia
Melatonin protects the BBB against hyperglycemia
Conclusions and prospects
Diabetes-induced AD has been called “type 3 diabetes” owing to the common risk factors, which include insulin resistance and hyperglycemia. Here, we reviewed the effect of melatonin in type 3 diabetes from various angles. Melatonin influences type 3 diabetes by 1) suppressing Aβ toxicity and tau hyperphosphorylation, 2) controlling insulin resistance and hyperglycemia, and 3) preventing hyperglycemia-induced BBB disruption. Hence, we suggest that melatonin would be a key in attenuating the pathogenesis of type 3 diabetes.
This study was supported by the Brain Research Program through the National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning NRF-2016M3C7A1905469 (B.K.) and a grant from 2016R1D1A1B03930394 (J.S.).
All sources of funding (the Ministry of Science, ICT & Future Planning NRF-2016M3C7A1905469 & - 2016R1D1A1B03930394) for the research declare the support of the funding in collecting references and in writing the manuscript.
Availability of data and materials
JS contributed to writing the preliminary draft of this manuscript. DJW revised the overall manuscript with a logical argument. BCK revised the manuscript as a whole. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Consent for publication
The authors declare that they have no competing interests.
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