TABLE 2.

Inflammatory changes associated with cerebral edema development during diabetic ketoacidosis

	Findings	Clinical implications/associations
Studies in animals
Systemic inflammation	In mice, DKA was associated with higher levels of inflammatory markers, including IL-6, IL-8, IL-10, CCL2, sE-selectin, sICAM-1, and sVCAM-1.82	Stimulation of brain endothelial cell line with DKA plasma was associated with increased ROS and activation of NF-κB, upregulation of pro-adhesive phenotype, and enhanced leukocyte rolling/adhesion, contributing to cerebrovascular endothelial cell dysfunction.82
Neuroinflammation	In rats: • Exposure to hyperglycemia before ischemic event was associated with significantly higher number of myeloperoxidase-positive cells within pial and parenchymal vessels and brain parenchyma.83 • Untreated DKA was associated with increased expression of GFAP, indicating reactive gliosis and activation of microglia; these findings intensified during DKA treatment with insulin/saline.84,85	• Pre-ischemic hyperglycemia triggers massive deposition of PMNs in post-ischemic brain, leading to increased PMN adherence to cerebral blood vessels, disruption of the BBB, and PMN migration into brain parenchyma, exacerbating underlying tissue injury.83 • In the setting of cerebral hypoxia, microglia produce several inflammatory cytokines, including IL-1β and TNF-α, ROS, and NO, which could exacerbate BBB dysfunction during reperfusion injury.84,85
Studies in humans
Systemic inflammation	DKA and hyperketonemia associated with: • Increased activation of peripheral T-lymphocytes86 • Elevated systemic levels of CRP and related markers of cardiovascular risk,87–92 pro-inflammatory cytokines,76,87–90,93,94 and ROS44,88,92 • Reduced levels of antioxidants44 • Complement activation45	DKA severity has been shown to correlate with systemic neutrophil activation and degranulation, leading to the release of vasoactive substances, such as proteinase-3, that degrade the BBB.102
Neuroinflammation	Fatal cases of DKA associated with: • Increased neuronal expression of cytokines, adhesion molecules, complement peptides,95–97 ROS,98–100 and receptor for AGEs101 • Localization of CCL2, NF-κB, and nitrotyrosine to the perivascular regions of the disrupted BBB66 • Microglial activation and astrocyte reactivity66	• Several cytokines and chemokines, including CXCL1 and IL-8, were found to facilitate leukocyte adhesion to cerebrovascular endothelium during DKA.103 • Alterations in the peripheral104 and neuronal105 expression of matrix metalloproteinases in DKA have been implicated in the disruption of the BBB, mediated by the degradation of tight junction proteins.

Abbreviations: AGEs, advanced glycation end products; BBB, blood–brain barrier; CCL2, chemokine (C-C motif) ligand 2; CRP, C-reactive protein; CXCL1, chemokine (C-X-C) motif ligand 1; DKA, diabetic ketoacidosis; GFAP, glial fibrillary acidic protein; IL, interleukin; NF-κB, nuclear factor-kappa B; NO, nitric oxide; PMN, polymorphonuclear lymphocyte; ROS, reactive oxygen species; sE-selectin, soluble endothelial selectin; sICAM-1, soluble intracellular adhesion molecule-1; sVCAM-1, soluble vascular cell adhesion molecule-1; TNF-α, tumor necrosis factor-alpha.