Nerve dysfunction and cell death in DN results from a complex myriad of events that are triggered by the metabolic imbalances associated with diabetes. Hyperglycemia, dyslipidemia, and/or insulin resistance promotes activation of the protein kinase C (PKC), polyol, advanced glycation end-product (AGE), poly (ADP-ribose) polymerase (PARP), and hexosamine pathways, as well as loss of insulin signalling, which culminate in deleterious effects on mitochondrial function and gene expression along with inflammation and oxidative stress.