The mechanisms of glycemic variability accelerate diabetic central neuropathy and diabetic peripheral neuropathy in diabetic rats.

The effect of glycemic variability (GV) on diabetic neuropathy, including diabetic central neuropathy and diabetic peripheral neuropathy (DPN), and the involved mechanism are not fully understood. In this study, a fluctuant hyperglycemia rat model was induced by alternate intraperitoneal injections of glucose and insulin. To assess diabetic central neuropathy, step-down type passive avoidance tests were conducted, and the expression levels of p-Tau, T-Tau, p-GSK3β, GSK3β, p-Akt, and Akt in the hippocampus were measured. To assess DPN, the motor nerve conduction velocity (MNCV) was measured, and the microstructure of the sciatic nerve was observed. Additionally, the expression levels of oxidative stress and inflammation indicators were detected in the sciatic nerve. We observed that both learning and memory abilities were disrupted by GV. GV promoted Tau phosphorylation and inhibited the Akt/GSK3β pathway in the hippocampus. Additionally, GV weakened the MNCV of the sciatic nerve, and the structures of both the myelin sheath and the axons in the sciatic nerve were disrupted. GV also significantly reduced the expression of superoxide dismutase (SOD) and increased the expression levels of malondialdehyde (MDA), of proinflammatory cytokines (TNF-α and IL-6) and of NF-κB. In conclusion, the present study highlighted that GV might induce diabetic central neuropathy through the hyperphosphorylation of Tau in the hippocampus by inhibiting the Akt/GSK3β pathway and that it may cause DPN through oxidative stress and inflammatory responses by activating the NF-κB pathway.