Hexokinase-2 Glycolytic Overload in Diabetes and Ischemia–Reperfusion Injury

Hexokinase-2 (HK2) was recently found to produce increased metabolic flux through glycolysis in hyperglycemia without concurrent transcriptional or other functional regulation. Rather, stabilization to proteolysis by increased glucose substrate binding produced unscheduled increased glucose metabolism in response to high cytosolic glucose concentration. This produces abnormal increases in glycolytic intermediates or glycolytic overload, driving cell dysfunction and vulnerability to the damaging effects of hyperglycemia in diabetes, explaining tissue-specific pathogenesis. Glycolytic overload is also activated in ischemia–reperfusion injury and cell senescence. A further key feature is HK2 displacement from mitochondria by increased glucose-6-phosphate concentration, inducing mitochondrial dysfunction and oxidative stress. This pathogenic mechanism suggested new targets for therapeutics development that gave promising outcomes in initial clinical evaluation. HK2 produces increased metabolic flux through glycolysis in hyperglycemia through glucose-mediated stabilization of HK2 to proteolysis.This produces abnormal increases in glycolytic intermediates or glycolytic overload, driving mitochondrial dysfunction and activation of hexosamine, protein kinase C, and dicarbonyl stress pathways.HK2-linked glycolytic overload explains tissue-specific pathogenesis in diabetes linked to vascular complications and contributes to pathogenesis in ischemia–reperfusion injury and cell senescence.This new pathogenic mechanism hypothesis suggested new targets for therapeutic development that gave promising outcomes in initial clinical evaluation.