Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from

deficient insulin secretion, insulin action, or both. (American Diabetes Association, 2010). Chiefly,
carbohydrate, lipid, and protein metabolism deteriorates, and various long‐term complications appear
in diabetes (Piero et al., 2014). Persistent hyperglycemia can generate oxygen species and cause
neuroinflammation in the brain (Pari et al., 2007). Hippocampal injury, reduction in gray matter density,
changes in white matter microstructure, and atrophy in brain structure have been reported in patients
with diabetes. These patients have higher prevalence of acute coronary syndrome, cerebral ischemic
stroke, and peripheral arterial disease than the nondiabetic individuals ( Zhang et al., 2008). The
disruption of the circadian oscillation of glucose metabolism is another feature of type 2 diabetes (Kreier
et al., 2007). Disrupted circadian rhythmicity and oxidative stress are closely linked when oxidative and
antioxidative balance is impaired (Marcheva et al., 2010). In addition, chronic hyperglycemia through
polyol pathway and increased formation of reactive oxygen species inducing a state of oxidative stress
have been proposed as a major pathophysiological link between progression of Type II diabetes mellitus
and the onset of diabetic complications (Yan et al., 2011). Oxidative stress results from an imbalance
between reactive oxygen species production and anti‐oxidation. Furthermore, oxygen free radical
generation due to non‐enzymatic protein glycosylation and auto‐oxidation of glucose can be seen in
diabetes mellitus (Ahmed et al., 2005). Animal studies have shown that brain of diabetic animals is more
sensitive to ischemic damage compared with normoglycemic animals because of the increased brain
oxidative stress (Gonzalez‐Correa et al., 2006). Therefore, antioxidant administration should be
postulated to prevent cerebral complications of diabetes. The main complications of DM are
nephropathy, retinopathy, and neuropathy (Schmidt, 2018). People with both type 1 and type 2
diabetes have been shown to have mild to moderate reductions in cognitive function as measured by
neuropsychological testing compared to non-diabetic controls. Type 2 diabetes (T2DM) has also been
associated with 50% increased risk of dementia (Biessels, 2006) Whether such an association is true for
people with type 1 diabetes (T1DM) is not yet known. Diabetic neuropathy (DN) affects more than 50%
of patients with diabetes and is defined as a set of clinical syndromes that affect different regions of the
nervous system. The worldwide prevalence of diabetes mellitus (DM) is increasing at an alarming rate.
According to data from the World Health Organization, diabetes will be the seventh leading cause of
death in 2030.

Insulin is a protein hormone that is synthesized in the β‐cells of Langerhans islets of pancreas (Duarte et
al., 2005). It is one of the most important hormones that play a key role in the control of glucose
homeostasis in the treatment of Type I diabetes mellitus (Rains et al., 2011). Insulin controls glucose
homeostasis by stimulating the glucose usage in muscle and adipose cells while reducing hepatic glucose
production through gluconeogenesis and glycogenolysis (Rains et al., 2011). This hormone also affects
cell permeability and protein metabolism (Dinççag et al., 2005). Although brain glucose metabolism is
independent from the effects of insulin, clinical outcomes in diabetes mellitus are multifactorial and are
related to both macrovascular and microvascular changes due to endothelial dysfunction leading to end‐
organ pathology (Alexandru et al., 2016).
Melatonin (NN-acetyl-5-methoxytryptamin) had been first identified as the hormone of the pineal gland.
Meanwhile, numerous additional sites of formation and a multitude of functions have been identified,
which exceed the first-discovered roles of this indoleamine as a melanosome-concentrating agent in fish
and amphibia and a mediator of the signal “darkness“ in the vast majority of vertebrates. Considerable
differences exist between melatonin formed in the pineal gland and in other organs, especially with
regard to tissue retention, local metabolism and release to the circulation. In mammals, the contribution
of extrapineal sources to circulating melatonin is usually low, mainly with the exception of the
gastrointestinal tract, from which the indoleamine is released at substantial concentrations, but only
under the influence of nutritional factors, in terms of a postprandial response.The amounts of gut-
derived melatonin which appear in the circulation can acutely exceed by far those secreted by the pineal
and may lead to central nervous actions, but their chronobiological effects remain weak, for reasons
related to the phase-response curve for melatonin.

In addition, melatonin augments the antioxidant defense system and down-regulates inflammatory
mediators. Several studies have demonstrated the neuroprotective action of melatonin in
neurodegenerative disorders, such as amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s
disease, and multiple sclerosis (Zhang Xuyan, 2017). In a previous study, melatonin was found to have a
neuroprotective effect against streptozotocin (STZ)-induced neurobehavioral and neurochemical
deficits. Melatonin has been implicated in cognitive events as learning process and memory formation
as well as ameliorating motor coordination after brain injuries (Bavithra, 2017). In the rat model of
hypoxia–ischemia, melatonin treatment efficiently decreases brain damage.

By virtue of its amphiphilicity, melatonin can easily cross the blood-brain barrier. It can enter the CNS
and the cerebrospinal fluid (CSF) via the choroid plexus. This should be particularly important after
administration of exogenous melatonin. To what extent the circulating hormone contributes, under
physiological conditions, to its brain concentrations is not fully understood, specially as the pineal itself
releases the indoleamine at much higher concentrations directly via the pineal recess to the third
ventricle. The appearance of melatonin in the third ventricle has been very recently demonstrated in
humans, but the amounts reported are relatively moderate (about 8.75 pg/mL). Even lower
concentrations were measured in the lateral ventricles. In a study comparing melatonin levels in mouse
serum and cerebral cortex, the cortical concentrations amounted to 1% or less of those found in serum.
Approximately the same ratio was found after administration of exogenous melatonin. One should,
however, be always aware that concentrations tell little about amounts taken up, since a compound
may readily disappear if it is rapidly

Melatonin metabolism in the CNS is particularly relevant for several reasons. The relative contribution of
concurrent catabolic pathways may be strongly influenced by conditions of inflammation and oxidative
stress. This is supported by findings on elevated levels of melatonin’s oxidation product N1-acetyl-N2-
formyl-5-methoxykynuramine (AFMK) in the cerebrospinal fluid of patients with meningitis . This
metabolite and also its secondary product, N1-acetyl-5-methoxykynuramine (AMK), have been shown to
possess cell-protective properties including beneficial effects in mitochondria. Moreover, numerous
publications have demonstrated the neuroprotective potential of melatonin under various experimental
conditions. For this purpose, elevated doses of melatonin strongly exceeding physiological levels have to
be used, especially under acute conditions requiring the prevention of neuronal dysfunction.

There have been various research on potential impact of melatonin on brain metabolism in
diabetes.Some of these research suggests that melatonin may have the following beneficial impact on
brain metabolism in diabetes:

Antioxidant Properties: Melatonin is a potent antioxidant and has been shown to reduce oxidative
stress, which is a common feature of diabetes. Oxidative stress can damage brain cells, and melatonin's
antioxidant properties may help mitigate this damage.

Neuroprotection: Melatonin has been investigated for its potential to protect nerve cells from damage
caused by high blood sugar levels in diabetes. It may have a neuroprotective effect, helping to prevent
or minimize cognitive impairment associated with diabetes.

Anti-Inflammatory Effects: Melatonin also exhibits anti-inflammatory properties. Inflammation plays a

role in the development and progression of diabetes-related complications, including those affecting the
brain. By reducing inflammation, melatonin might help preserve brain health.

Glucose Metabolism: Some studies suggest that melatonin may influence glucose metabolism in the
brain, potentially improving insulin sensitivity and glucose utilization.

Furthermore, melatonin is responsible for the establishment of an adequate energy balance mainly by
regulating energy flow to and from the stores and directly regulating the energy expenditure through
the activation of brown adipose tissue and participating in the browning process of white adipose tissue.
The reduction in melatonin production, as during aging, shift-work or illuminated environments during
the night, induces insulin resistance, glucose intolerance, sleep disturbance, and metabolic circadian
disorganization characterizing a state of chronodisruption leading to obesity.

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