Insulin Resistance and Oxidative Stress in the Brain: What's New?

Abstract

The latest studies have indicated a strong relationship between systemic insulin resistance (IR) and higher incidence of neurodegeneration, dementia, and mild cognitive impairment. 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 neuronal redox imbalance and oxidative damage. In this mini review, we provide a schematic overview of intracellular oxidative stress and mitochondrial abnormalities in the IR brain. We highlight important correlations found so far between brain oxidative stress, ceramide generation, β-amyloid accumulation, as well as neuronal apoptosis in the IR conditions.

Keywords: brain; insulin resistance; mitochondrial dysfunction; oxidative stress.

Figure 1

The brain as a specific target for insulin resistance and oxidative stress. The brain is particularly sensitive to the free radical attack due to its increased oxygen consumption, limited antioxidative mechanisms, as well as high levels of polyunsaturated fatty acids (PUFAs). In IR brain, overproduction of reactive oxygen species (ROS) leads to oxidative damage associated with ATP depletion, activation of pro-inflammatory cytokines, accumulation of protein aggregates, as well as neuronal apoptosis. Abbreviations: IR, insulin resistance; PUFAs, polyunsaturated fatty acids.

Figure 2

Metabolic disturbances in peripheral insulin resistance as a source of brain oxidative stress. Under insulin resistance (IR) conditions, enhanced plasma fatty acids (FAs), hyperglycaemia, and hyperinsulinemia promote glucotoxicity and lipotoxicity (especially ceramide accumulation) leading to the activation of nuclear factor κB (NFκB) and pro-inflammatory signalling (e.g., MAP-kinases). Not only does it intensify the inflammation, but it also increases the formation of reactive oxygen species (ROS). Abbreviations: AGE, advanced glycation end products; AMPK, AMP-activated protein kinase; FAs, fatty acids; GSK3β, glycogen synthase kinase 3 beta; IKK, IκB kinase; IRS-1, insulin receptor substrate 1; IR, insulin resistance; JNK, c-Jun terminal kinase; MAPK, mitogen-activated protein kinases; mETC, mitochondrial electron transport chain; NFκB, nuclear factor κB; PKC, protein kinase C; PI3-K-Akt, phosphatidylinositol 3-kinase/Akt; ROS, reactive oxygen species.

Figure 3

Crosstalk between ceramide, oxidative stress, and the brain insulin resistance. Ceramide plays a key role in the induction of brain IR. Peripheral IR is associated with an elevated ceramide generation. Ceramide like other neurotoxic lipids can pass through the blood-brain-barrier (BBB), contributing to the brain IR via liver-brain axis of neurodegeneration. In IR brain, ceramide can induce neuronal apoptosis and, similarly to Alzheimer’s disease, accumulation of amyloid β-peptides (Aβ). However, a key mediator of Aβ-neurotoxic effects may not be the ceramide but rather oxidative stress. It has been demonstrated that Aβ induces activation of NADPH oxidase (NOX) associated with glutathione (GSH) depletion, lipid and protein oxidation, disturbances in glucose metabolism, as well as mitochondrial abnormalities. Abbreviations: Aβ, amyloid β-peptides; APP, Aβ precursor protein; BBB, blood-brain-barrier; BACE1, β-secretase; ER, endoplasmic reticulum; FAs, fatty acids; GSH, reduced glutathione; GSSG oxidised glutathione; NOX, NADPH oxidase; SMases, sphingomyelinases.

Figure 4

Mitochondrial dysfunction in brain insulin resistance. The results of recent studies indicate the role of mitochondrial abnormalities in the brain IR. Increased production of mitochondrial ROS (mROS), cytochrome c release, as well as functional and ultrastructural changes of mitochondria have been confirmed in IR brain. Interestingly, brain mitochondrial dysfunction and Aβ accumulation may be responsible for disturbances in apoptosis, synaptic plasticity, cognitive decline, and cerebral degeneration in IR patients. Abbreviations: Aβ, amyloid β-peptides; APAF1, apoptotic protease activating factor 1; BAD, Bcl-2-associated death promoter; BAK, Bcl-2 homologous antagonist killer; BAX, Bcl-2-associated X protein; cyt c, cytochrome c; mROS, mitochondrial ROS; mtDNA, mitochondrial DNA; ROS, reactive oxygen species.