Possible role of exogenous melatonin in preventing more serious COVID-19 infection in patients with type 2 diabetes mellitus

18-21 SUMMARY COVID-19 infection is more severe in patients with type 2 diabetes mellitus (DM2). The severity of this viral infection is associated with an intense inflammatory activity. DM2 is a disease that also determines a greater degree of systemic inflammation. This is due to hyperglycemia, the higher prevalence of sleep disorders and also the low levels of melatonin, a substance with anti-inflammatory actions, in these patients. In this article, we suggest that exogenous melatonin may have an important anti-inflammatory role in preventing severe forms of COVID -19 in patients with DM2.


INTRODUCTION
The COVID-19 pandemic manifests itself with particularly adverse outcomes for some groups.Patients with heart disease, lung disease, senility, obesity, and DM2 frequently evolve to severer forms of COVID-19, with respiratory failure and death 1 .Understanding such vulnerability can be an important step to improve the knowledge about the Covid pathophysiology.COVID-19 presents an initial infectious phase, which later evolves into a second phase inflammatory, with greater repercussion and severity.The risk groups present pathologies that bear a common link.They exhibit a previous significant increase in inflammatory activity, which combined with the inflammation generated by COVID-19, could result in a worsening evolution 2 .
In diabetes mellitus, systemic inflammation is well known as it results in chronic complications of the disease.Part of this inflammation is due to hyperglycemia 3 .Another significant part of this inflammation is secondary to sleep disorders (sleep deprivation, insomnia, sleep-related breathing disorders, and circadian rhythm sleep-wake disorders) very prevalent in these patients 4 .In addition to a greater circulation of inflammatory agents, both DM2 and sleep disorders determine a lower amount of an important anti-inflammatory agent: melatonin [5][6][7] .The patient with DM2, therefore, has two reasons for presenting with higher inflammatory status: more inflammatory agents and less anti-inflammatory agents.This can justify the development more likely of severe acute inflammatory reactions in the second phase of COVID-19.In this context, melatonin with its anti-inflammatory properties can be a promising drug.In addition to its direct anti-inflammatory activity 7,8 , melatonin can treat sleep disorders common in these patients [9][10][11][12] which would further contribute to reducing baseline inflammation.In this article, we will discuss the pathophysiological basis and perspectives for the prophylactic use of melatonin to prevent severe forms of COVID-19 in patients with DM2.We hypothesized that the use of melatonin even before infection can protect patients with diabetes from severe forms of the disease.

COVID-19 AND INFLAMMATION: PATHOPHYSIOLOGY
The most severe manifestations of COVID-19, such as acute respiratory syndrome, appear to be associated with an exacerbated inflammatory response, which occurs after an initial phase of mild symptoms, such as cough and fever 13,14 .This response has been called a cytokine storm.In vitro, it was shown that initially there is a delay in the production of cytokines, such as interferons, and recruitment of CD8 T cells, responsible for immune response to infections.These mechanisms allow greater initial viral replication and could explain the paucity of symptoms at the initial phase, with low inflammatory activity.Subsequently, there is a rapid increase in cytokines and inflammatory cells in tissues, leading suddenly to acute and intense clinical manifestations.Interferon alpha/beta, interleukins 1, 6, 8, reactive oxygen species (ROS), oxidative enzymes, and tumor necrosis factors, produced by macrophages, take part in this immune response 15 .The acute inflammatory storm is responsible for the multiple organ failure seen in COVID-19.Inflammatory markers, such as ferritin and D-dimer, and a drop in the number of platelets appear as capable of predicting this intense inflammatory activity 16 .Currently, no medications were competent to prevent serious forms of COVID-19 infection.A recent study, for example, showed that hydroxychloroquine -one of the most discussed medications in scientific and political circles ¾ did not show benefits for the prevention of COVID-19 17 .Finding a drug that reduces the chance of severe infection seems particularly vital in groups at risk, such as those composed of patients with greater previous baseline inflammatory activity: DM2, sleep disorders, or both conditions.

DIABETES MELLITUS, SLEEP AND INFLAMMATION
DM2 is a disease characterized by chronic hyperglycemia.This hyperglycemia leads to an inflammatory and also an immune imbalance.The inflammation occurs by activation of the polyol pathway, increased formation of end products of advanced glycosylation and protein C kinase isoforms, and increased influx of ROS into cells.ROS induces epigenetic changes by altering pro-inflammatory genes, thus perpetuating the inflammatory process even after hyperglycemia is resolved.Immunological imbalance can be observed by helper T cells 1 and 2 which produce an excess of anti and pro-inflammatory factors 18 .Similar imbalances are present in severe forms of COVID-19, where there is excessive inflammatory activity and anomalous immunomodulation sometimes inhibits and other times over-activates inflammatory mechanisms 19 .
In DM2, in addition to hyperglycemia, frequent sleep disorders contribute to a chronic elevation of the basal inflammatory status.Previous studies found that sleeping fewer hours per night can lead to activation of interleukins and tumor necrosis factors.Not only shorter sleep duration, but poor sleep quality can increase inflammatory status.Finally, sleep apnea, through intermittent nocturnal hypoxemia, can lead to the exacerbation of chronic systemic inflammation [5][6][7] .Therefore, as sleep disorders are frequent in DM2 is reasonable to think that this fact may contribute to severe forms of COVID-19 that are related to a higher inflammatory status.

MELATONIN AND COVID 19 PREVENTION: WHAT WOULD BE THE RATIONALE?
Some data suggest a possible protective and preventive role of melatonin in DM2 against COVID-19 [19][20][21][22] .Microbats of the genus Rhinolophus are natural carriers of coronaviruses.These animals act as hosts and can transmit coronaviruses that are highly pathogenic to humans and livestock.Despite carrying coronavirus for long periods, these bats normally do not suffer from clinical symptoms and consequences of the infection 23 .Because they rest in ill-illuminated caves during the day and are active in the darkness of the night, they are constantly protected against sunlight.The available data indicate that their melatonin is kept at much higher levels in comparison to those in humans, throughout day and night 23 .The improved immunological ability against coronavirus pathology observed in these bats might bear relationships to this continuously higher level of melatonin in these nocturnal mammals.The most serious forms of COVID-19 occurred in older people and melatonin levels tend to reduce importantly as age advances 21 .Previous studies have shown that low levels of melatonin are associated with an increased risk of DM2 24,25 .This data is reinforced by studies that showed a higher risk of DM2 related to the presence of melatonin receptor 2 (MTR2), a polymorphism present in the pancreatic beta cell 26 .Would be lower levels of melatonin associated with a higher prevalence of severe symptoms in DM2?
One of the consequences of COVID-19 infection is the inability of macrophage mitochondria to produce melatonin.These cells adopt aerobic glycolysis, becoming highly inflammatory and hindering the production of coenzyme A from pyruvate.Melatonin absence at mitochondrial level prevents neutralization of free radicals and inflammatory cytokines capable of tissue damage 19 .In addition, melatonin has vasodilator activity-dependent and independent of nitric oxide.This latter effect would be associated with activation of the prostaglandin pathway.This mechanism would also be associated with the antioxidant and anti-inflammatory activities of melatonin and would prevent lesions in pulmonary vasculature at endothelial level, thus avoiding progression to pulmonary hypertension and cardiac injury 27 .Some authors suggest that melatonin could be used in sleep-deprived, inflamed patients to prevent lung injuries in the case of infection by COVID-19 15 .In advanced stages of infection by COVID-19, it is also postulated that melatonin has an effect to suppress the NOD-like receptor 3, a receptor capable of amplifying inflammation 20 .Thus, there would be suppression of cytokine storm in the second phase of the disease.In elderly DM2 sleep-deprived patients, melatonin levels are lower, NOD-like receptor 3 (NLRP3) is not inhibited, and greater COVID-19 severity is expected.Melatonin has a mild profile of side-effects and drug interactions and is not unrecommended in the 2019 edition of the American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults 28 .Future clinical trials could determine its therapeutic role here.

CONCLUSION
We conclude that melatonin modulates protective mechanisms against COVID-19.Melatonin can be safely administered to DM2 sleep-deprived elderly patients.It is not listed in the 2019 edition of the American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults.It has good tolerability and the incidence of side effects is low.Melatonin can be part of preventive interventions to avoid the progression from mild to severe forms of COVID-19 in association with other health measures.Randomized clinical trials are needed to assess whether such actions of exogenous melatonin would be similar to the paracrine actions of these substances.