Figure 2.

Pathophysiology of neuronal cell death and dysfunction during diabetes development. Uncontrolled hyperglycemia, hyperlipidemia and impaired insulin signaling occur during the development of diabetes and diabetic neuropathy. Hyperglycemia activates glycolysis, oxidative phosphorylation and aldose reductase pathways, resulting in the formation of oxidative stress, glycation end-products (AGE) and protein kinase c (PKC)-mediated cell signaling molecules. Elevated levels of LDL, FFA and TG activate oxidative stress, and impaired insulin signaling induces nerve dysfunction via inhibition of neurotrophic signaling. PKC, protein kinase C; AGE, advanced glycation end products; LDL, low-density lipoprotein; FFA, free fatty acid; TG, triglyceride; RAGE, receptor for advanced glycation end products; LOX, oxidized LDL receptor 1; PI3K, phosphatidylinositol 3-kinase.