High glucose flux through constitutive glucose transporters on endothelial cells overwhelms the mitochondrial electron transport system. Excess mitochondrial substrate flux results in the generation of reactive oxygen species that cause DNA strand breaks and activation of PARP. PARP ribosylates and inactivates GAPDH, thereby disrupting normal glucose metabolism. Inactivation of GAPDH effectively shunts glucose into the polyol pathway and leads to activation of PKC and accumulation of AGEs and glucosamine. DAG, diacylglycerol.