Oxidative stress: The nexus of obesity and cognitive dysfunction in diabetes

Abstract

Obesity has been associated with oxidative stress. Obese patients are at increased risk for diabetic cognitive dysfunction, indicating a pathological link between obesity, oxidative stress, and diabetic cognitive dysfunction. Obesity can induce the biological process of oxidative stress by disrupting the adipose microenvironment (adipocytes, macrophages), mediating low-grade chronic inflammation, and mitochondrial dysfunction (mitochondrial division, fusion). Furthermore, oxidative stress can be implicated in insulin resistance, inflammation in neural tissues, and lipid metabolism disorders, affecting cognitive dysfunction in diabetics.

Keywords: cognitive dysfunction in diabetes; insulin resistance; lipid metabolism disorders; neuroinflammation; obesity; oxidative stress; reactive oxygen species.

Figure 1

The link between obesity and oxidative stress. Obesity can induce the biological process of oxidative stress by disrupting the adipose microenvironment, mediating chronic inflammation, and mitochondrial dysfunction. The process is probably that excess glucose and free fatty acids suppress the TCA cycle, leading to an increase in the production of acetyl CoA. Excess acetyl CoA stimulates mitochondrial dysfunction, resulting in an increase of ROS within the cell, this change may activate many factors, the nuclear factor κB is the main inflammatory factor.TCA cycle, Tricarboxylic Acid cycle; acetyl CoA, Acetoacetyl coenzyme A; ROS, Reactive Oxygen Species; NF-κB, nuclear factor κB.

Figure 2

Oxidative stress can be involved in insulin resistance, neuroinflammation, lipid metabolism disorders leading to diabetic cognitive dysfunction. Oxidative stress reduces GLUT-4 expression and the translocation of GLUT-4 to the cell membrane, decreasing insulin sensitivity; In the brain, insulin activates the PI3K/PDK1/AKT and the PI3K/AKT/mTOR signaling pathway to inhibit apoptosis and promote neuronal development and survival, which are inhibited when insulin is resistant and increase the production of inflammatory factors. Neuroinflammation is associated with excessive microglia activation. activation of IL1-R1 signaling pathway, NLRP3/IL-1β signaling pathway, NK-κB signaling pathway and release of pro-inflammatory factors exacerbate neuroinflammation and neuronal damage in the brain. The inhibition of TLR4/AKT/mTOR signaling pathway inhibits cellular autophagy as well as promotes neuroinflammation and microglia apoptosis. Diabetic cognitive dysfunction is also exacerbated by the presence of impaired lipid metabolism in the brain. CD36 recognizes oxidized low-density lipoprotein receptors (TLRS) and triggers a toll-like response to stimulate sterile inflammation. Meanwhile, LCN2 is mainly produced in glial cells of the brain under oxidative stress. It promotes cellular neuroinflammation by activating the NF-kB pathway as well as the STAT3 signalling pathway to promote microglia activation. IR, Insluin resistance; GLUT4, facilitated glucose transporter member 4; PI3K, phosphatidylinositol 3' -kinase; PDK1, pyruvate dehydrogenase kinase isoform 1; AKT,  Protein Kinase B; mTOR, mammalian target of rapamycin; TLR4, toll-like receptor 4; IL1-R1, interleukin 1 receptor type I; NLRP3,NLR family pyrin domain containing 3; NF-κB, Nuclear factor kappa B; LCN2, Lipocalin 2; STAT3, signal transduction and transcription 3; CD36, Platelet glycoprotein 4.