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Advanced Neurology Inflammation in diabetic stroke: Pathogenesis

Figure 1. Schematic diagram depicting the mechanism of atherosclerosis formation under the influence of diabetes (denoted by red)
Abbreviations: AGE: Advanced glycation end products; eNOS: Endothelial nitric oxide synthase; IL: Interleukin; LDL: Low-density lipoprotein; NF-κB:
Nuclear factor kappa B; NADPH: Nicotinamide adenine dinucleotide phosphate hydrogen; RAGE: Receptor for advanced glycation end products; TNF-α:
tumor necrosis factor alpha.

of the most pathological importance and are abundantly sorbitol and in the process depletes cellular nicotinamide
expressed on vascular endothelial cells. The high levels adenine dinucleotide phosphate hydrogen levels, which
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of AGEs induce higher levels of RAGE expression in is a cofactor for the antioxidant glutathione, resulting in
diabetic patients. 18,20,21 AGE-RAGE binding activates reduced cellular resistance to oxidative stress. Binding
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multiple signaling pathways. One of the most important of AGEs to RAGEs also plays a pivotal role in elevating
20
in endothelial cells is NF-κB pathway, as discussed above, cytosolic ROS production, resulting in oxidative stress. 26
resulting in the synthesis of adhesion molecules and The hallmark of type 2 diabetes is insulin resistance.
chemoattractants to recruit inflammatory cells. There is Although the underlying mechanisms of insulin resistance
evidence that diabetic patients have elevated NFκB gene development are not fully understood, obesity is a
expression. 22 common cause of insulin resistance and type 2 diabetes.
It is widely known that hyperglycemia gives rise to In addition to being a source of energy storage, white
oxidative stress. Under normal physiological conditions, adipose tissue also secretes several humoral factors, with
there are many highly reactive oxygen-derived molecules leptin and adiponectin being the most common. The
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called reactive oxygen species (ROS), including nitric Jackson Heart study showed that individuals with type 2
oxide (NO). NO is a potent vasodilator, generated by diabetes had significantly higher levels of leptin and lower
NO synthases in the endothelium (eNOS). In addition, levels of adiponectin. Leptin is a well-known “satiety
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NO also inhibits platelet aggregation by increasing cyclic signal” that enhances energy expenditure. Leptin has
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guanosine monophosphate, thus lowering intracellular a structure similar to IL-6. In individuals with type 2
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Ca , and reducing inflammation by interfering with the diabetes, hyperleptinemia accelerates the development
2+ 23
adhesion cascade. It is important to note that the roles of atherosclerosis primarily by increasing the expression
24
of ROS are related to their steady-state concentrations of adhesion molecules and inflammatory cytokines
and the ability of cellular antioxidant systems to regulate and augmenting oxidative stress. On the other hand,
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their activities. Hyperglycemia drives mitochondrial adiponectin increases insulin sensitivity by simulating
dysfunction and causes uncoupling of eNOS, resulting in glucose uptake and fatty acid oxidation in skeletal muscles;
eNOS reducing NO production and generating high levels reduces inflammation by inhibiting the activation of
of ROS in the form of superoxide. 25,26 Hyperglycemia can NF-κB; and may reduce oxidative stress by inhibiting the
also trigger the polyol pathway, which converts glucose to inducible NO synthases (iNOS). 33,34

Volume 3 Issue 2 (2024) 3 doi: 10.36922/an.1683