*2.2.1. Hyperglycemia-induced inflammation*

In diabetes, hyperglycemia can induce inflammation via different mechanisms [42]. The metabolic defects underlying diabetes cause mitochondrial superoxide overproduction in endothelial cells of blood vessels. This increased superoxide production leads to the activation of five major pathways involved in the pathogenesis of complications: polyol pathway flux, increased formation of advanced glycation end products (AGEs), increased expression of the receptor for AGEs and its activating ligands, activation of protein kinase C (PKC) isoforms and overactivity of the hexosamine pathway [43].

Hyperglycemia leads to increased reduction of glucose to sorbitol by aldose reductase with nicotinamide adenine dinucleotide phosphate (NADPH) consumption [44]. The cellular antioxidant capacity relies on the energy provided by NADPH to the glutathione and thioredoxin antioxidant systems. Thus, NADPH decrement will result in reduced antioxidant capacity and increased oxidative stress [44].

In endothelial cells, vascular smooth muscle cells, monocytes and macrophages, the intracellular synthesis of diacylglycerol is increased in hyperglycemia, leading to the activation of the PKC pathway [45, 46]. In monocytes, there is a subsequent release of the integrins CD11b, CD11c, and CD14 [47, 48]. CD11b or CD11c receptor occupation on the surface of human monocytes stimulates cell-specific pro-inflammatory pathways such as secretion of IL-8, macrophage inflammatory protein (MIP)1α and MIP1β [49]. CD14 + CD16+ monocytes are also linked with pro-inflammatory conditions [50].

Hyperglycemia also upregulates toll-like receptor (TLR) activity through an increment in ROS augmenting inflammation. In human monocytes, Dasu and colleagues [51] reported that high glucose induces TLR2 and TLR4 expression through PKC activation, by stimulating NADPH oxidase (NOX). Several other studies have demonstrated that under hyperglycemic conditions, reducing ROS and specifically NOX activity reduced TLR expression and activity [52, 53].

AGEs are generated in vivo as a normal consequence of metabolism, but their formation is accelerated under conditions of hyperglycemia, hyperlipidemia, and increased oxidative stress [54–57]. AGEs are highly reactive and can trigger inflammation by generating particularly TNF-α and IL-6 [58]. In addition, AGEs activate their receptors/binding sites (RAGE and lactoferrin-like polypeptide complex) in endothelial cells, monocytes, and macrophages leading to the activation of MAPK and NF-κB. AGEs also enhance the formation of oxidized low-density lipoprotein (oxLDL) and during hyperglycemia the expression of LOX-1 on monocytes and macrophages increases. These processes further facilitate the uptake of oxLDL by macrophages, thus increasing inflammation [59, 60].

Another important mechanism to cause hyperglycemia-induced endothelial dysfunction is the redox-dependent activation of endothelial NLRP3 inflammasomes [61]. Endothelial tight junction disruption in diabetes requires NLRP3 inflammasomes. High glucose activates NLRP3 inflammasome in endothelial cells via ROS production. Reducing ROS production abolished high glucose-induced inflammasome activation, tight junction disruption, and endothelial hyperpermeability in endothelial cells. The clinical potential of targeting inflammasome signaling axis for prevention of the early onset of diabetic vasculopathy is evident [61].
