1. Introduction
It is widely recognized that insulin resistance (IR) plays a key role in the development of T2DM and its organ-related complications [5,6]. Thus, an explanation of IR pathogenesis is of great clinical significance.
Although for many years the brain has been considered an insulin-insensitive organ, it is now known that insulin acts a critical role in the central nervous system (CNS) participating in neuronal survival, neuroplasticity, memory, and cognitive functions [10,12,13,14]. Additionally, recent studies have demonstrated that peripheral IR results in loss of the brain function, which indicates strong relationship between metabolic disturbances and cerebral degeneration, cognitive impairment, depression, as well as Alzheimer’s disease (AD) [7,9,15,16,17,18]. It is suggested that one possible common denominator of all these conditions could be chronic oxidative stress [7,8,9,15,16,17,18].
2. Insulin Role in the Brain
As demonstrated in numerous studies, insulin action on the brain includes food intake regulation, feeding behavior, body weight, as well as energy homeostasis [12,14,24,27]. These effects may be mediated by two major components of the brain insulin transduction systems: phosphatidylinositol-3-kinase (PI3K)/Akt pathway and mitogen-activated protein kinases/Ras pathway (MAPK/Ras) [12,28].
However, some of insulin actions are specific for the CNS. Indeed, insulin has several neuronal roles: provides neuronal survival, participates in synaptic plasticity, and regulates the brain functioning including memory, cognition, learning, as well as attention [14,26,29,30]. It was shown that insulin can modulate neuronal activity through various molecular mechanisms [12,14,31,32]. This hormone affects neurotransmitter receptor density, inhibits norepinephrine and stimulates serotonin reuptake in the CNS synapses [12,33]. It also modulates long-term potentiation (LTP) and long-term depression (LTD) by reducing the amount of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors for glutamate as well as by stimulating the translocation of GABA (γ-aminobutyric acid) receptors in the post-synaptic membrane [12,31,32].
Interestingly, insulin in the brain may origin not only from pancreatic β-cells, but also can be synthesized de novo in the neurons and glial cells [12,14,25].
Studies conducted on brain GLUT-4 knockout (BG4KO) mice also suggest an important role of GLUT-4 in the regulation of systemic glucose level [36]. Nevertheless, there is no convincing evidence that transport and utilization of neuronal glucose is regulated by the insulin-mediated pathways. However, it should be emphasized that, regardless of the plasma insulin level, cerebral insulin also determines many metabolic effects via modulation of the vagal and sympathetic efferent fibres [37]. These actions include suppression of hepatic glucose production, hepatic triglyceride secretion, as well as lipolysis in the adipose tissue [26,30,37].
3. Brain Insulin Resistance
Indeed, it has been demonstrated that peripheral IR (or high circulating insulin level) alters the function of the blood-brain barrier (BBB) by reducing the level of endothelial insulin receptors and decreasing the BBB permeability to insulin [43,44]. This results in the impairment of physiological insulin functions as well as increased BBB permeability to many substances [26,27].
Although many causes of cerebral IR have been proposed to this day, the only confirmed explanation is ceramide accumulation in the brain tissue [11,16,45,46].
Elevated synthesis of neuronal ceramide associated with impaired insulin signalling was observed not only in vitro and in animal models of IR, but also in the brain of IR patients [8,41,57,58].
Briefly, ceramide activates several serine-threonine kinases (e.g., c-Jun N-terminal kinases (JNKs) and IκB kinase (IKK)) able to phosphorylate serine and thus inhibits insulin receptors substrates (mainly IRS-1) [46,60,61,62]. Consequently, ceramide downregulates Akt phosphorylation and kinase activity via induction of protein phosphatase 2A (PP2A) as well as activates interleukin-1β converting enzyme (ICE)-like proteases, resulting in the disruption of insulin signalling pathway and promotion of neuronal apoptosis [16,54,62].
4. Alzheimer’s Disease as a Type 3 Diabetes
It has been demonstrated that many abnormalities in AD pathology (e.g., increased tau phosphorylation, disturbances in energy metabolism, neuronal growth as well as synaptic plasticity) may result from impaired insulin signalling in the CNS. Indeed, in AD brain, cerebral insulin/IGF resistance leads to increased activation of GSK-3β [70,75,76]. It was shown that stimulation of GSK-3β promotes hyperphosphorylation of tau protein, and therefore induces tau misfolding and fibril aggregation in the brain [70,75].
5. Oxidative Stress in the Brain Insulin Resistance
The latest clinical studies have shown a strong relationship between whole body IR and higher incidence of neurodegeneration, dementia, depression, and mild cognitive impairment [7,9,15,16,17,18,46]. Although some of these abnormalities could be explained by chronic hyperglycaemia, hyperinsulinemia, dyslipidaemia, and/or prolonged whole body inflammation, the key role is attributed to the mitochondrial dysfunction and brain oxidative stress [7,8,9,15,16,17,18,85,86,87].
Under IR conditions, disturbances in enzymatic and non-enzymatic antioxidants as well as the increased content of oxidative modification products have been reported in serum/plasma [93,94,95,96,97] as well as liver, muscles, adipose tissue, and brain tissue [9,86,93,96,97,98,99]. However, of all body organs, the brain is particularly sensitive to the free radical attack [100,101].
The abovementioned, all together, may predispose neurodegeneration and/or neuronal apoptosis (Figure 1).
Interestingly, lowered GSH levels (with a simultaneous increase in GSSG (oxidized glutathione) levels) were reported not only in the IR brain, but also in patients with AD, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis and Huntington’s disease [55,107,108,109,110,111,112]. It is postulated that disturbances in glutathione metabolism may result in the impairment of cerebral functioning in both IR and neurodegenerative diseases [110,111]. This fact is not surprising because GSH is the most important of the brain’s antioxidants [112,113]. This compound, in addition to the antioxidant properties, also participates in the regeneration of other free radical scavengers (e.g., vitamins C and E), regulates gene expression (including the insulin signalling proteins), maintains sulfhydryl groups (-SH) in the reduced state, as well as affects proliferation, differentiation and neuronal apoptosis [109,111,112,114]. However, also advanced glycation end products (AGE, products of glycation and oxidation by reducing sugars) are an important link between IR and cerebral degeneration [115,116,117]. It has been demonstrated that the accumulation of protein aggregates leads to morphological changes in the brain tissue and increases the production of pro-inflammatory cytokines and chemokines [115,118,119,120]. Moreover, it has been shown that AGE may increase production of free radicals by inducing the activity of NADPH oxidase (NOX), which is the main source of ROS in neurons and glial cells [116,121,122].
6. Metabolic Disturbances as a Link between Brain Insulin Resistance, Oxidative Stress and Neurodegeneration
According to the current state of knowledge, metabolic disorders accompanying peripheral IR are thought to induce neuronal oxidative stress.
Considering that the brain is particularly sensitive to the redox abnormalities, peripheral oxidative stress can affect the induction of neuronal oxidative stress (Figure 2). Especially, it is promoted by the increased BBB permeability under IR/hyperglycaemic conditions.
Due to the fact that ceramide mediates IR and can cross the BBB, there is a relationship between peripheral IR and cerebral degeneration [8,45,46]. However, it has been demonstrated that exposure to short-chain ceramide results not only in neuronal IR, but also inflammation, mitochondrial dysfunction, and free radical-mediated damage [8,16,45,70,143].
However, ceramide can also enhance formation of amyloid β-peptides through posttranslational stabilization of β-secretase (BACE1), which stimulates proteolytic modifications of Aβ precursor protein (APP) [60,61,146,147]. It is well known that deposition of Aβ protein plays a key role in the neurodegeneration in AD. Nevertheless, increased Aβ level was also reported in the IR patients [67,148].
Interestingly, a key mediator of Aβ-neurotoxic effects may not be directly related to ceramide but rather to oxidative stress (Figure 3). The resulted Aβ peptide highly up-regulates NADPH oxidase (NOX) generating a large amount of superoxide anions (O2−•) associated with GSH depletion, mitochondrial abnormalities, and oxidation of lipids, proteins, and nucleic acids [46,60,61,146].
7. Mitochondrial Abnormalities in the Brain Insulin Resistance
Mitochondria play a vital role in energy homeostasis of the cell. In addition to the bioenergetic processes, they also participate in insulin signalling, cell death/survival control, as well as are the main site of ROS generation in the cell during respiratory reactions in mETC. Therefore, it is not surprising that mitochondrial abnormalities are highly related to the development of peripheral IR [5,134,160,161]. It is well known that in IR/obese patients, excessive supplies of glucose and FAs contribute to the higher formation of mitochondrial ROS (mROS) produced as by-products of mETC [136,137,160]. Under these conditions, particularly large amounts of superoxide anion (O2−•) are formed, which not only oxidizes cell components but also inhibits the activity of glycolytic enzymes [160].
Several studies reported that mROS overproduction enhances the accumulation of amyloid β-peptides and induces oxidative damage to proteins, lipids and nucleic acids in the IR brain [16,153,165,166].
8. Conclusions
Several studies demonstrated that brain IR is inextricably linked to oxidative stress associated with accumulation of ceramide and protein aggregates, activation of pro-inflammatory cytokines, mitochondrial dysfunction, as well as neuronal apoptosis. It is believed that ROS overproduction occurs due to metabolic abnormalities accompanying peripheral IR and with an impaired mitochondrial activity in the IR brain. Recent studies have also shown that oxidative stress enhances the accumulation of amyloid β-peptides as well as decreases in dendritic spine density and long-term potentiation (LTP) in the IR brain. Therefore, redox imbalance may play a key role in cerebral degeneration, cognitive impairment, and increased incidence of Alzheimer’s disease in IR patients. Although several studies found the relationship between neuronal oxidative stress and the brain IR, it remains unclear whether redox imbalance is a primary cause of brain IR. We must not ignore the fact that the brain oxidative stress may also be the consequence of peripheral/brain IR. Hence, further studies are needed to better understand the role of oxidative stress in the IR brain as well as indicate the benefits of the use of antioxidant supplements.
Referência :
(1) Int J Mol Sci. 2019 Feb 18;20(4):874.
