Hexokinase-2-glycolytic overload axis in brain disorders exacerbated by diabetes

Subjects with diabetes have an increased risk of dementia, Parkinson's disease, and stroke. In the central nervous system, there is increased inflammation, blood-brain barrier permeability, amyloid-β and α-synuclein deposition, and decreased neuronal synaptogenesis and survival. The role of hexokinases in controlling glucose metabolism therein is often overlooked. We propose that hexokinase-2 dysfunction-driven glycolytic overload is critically involved. This increases glycolytic intermediates in astrocytes, microglial cells, microvessel endothelial cells, and pericytes, stimulating mitochondrial dysfunction, protein O-linked β-N-acetylglucosaminylation, protein kinase C phosphorylation, and methylglyoxal-induced unfolded protein response and NOD-, LRR-, and pyrin domain-containing protein 3 inflammasome activation. Therapeutic prevention is achieved through activation of transcription factor nuclear factor erythroid 2-related factor 2, increasing the expression of glucose-6-phosphate (G6P) dehydrogenase, glyoxalase 1, and antioxidant enzymes. This diverts excess G6P to the pentose phosphate pathway, methylglyoxal to the glyoxalase pathway, and counters oxidative stress, respectively.