The effect of insulin-induced hypoglycemia on spontaneous peripheral neuropathy in aged mice was examined. Ninety-five-week-old female B6C3F1 mice were infused subcutaneously for 2 weeks with 40 or 80 IU / kg / day of insulin with a micro osmotic pump. Blood glucose level was decreased during the infusion(4.3-6.8 mmol / L in mice receiving 40 IU / kg / day of insulin or 2.4-5.4 mmol / L in mice receiving 80 IU / kg / day of insulin versus 6.5-7.6 mmol / L in control mice). In histopathological examination, axonal degeneration and / or remyelination were observed in a small number of nerve fibers of control mice. Similar nerve fiber lesions were observed in mice receiving 40 IU / kg / day of insulin, whereas severer lesions with an increase in segmental axonal degeneration of nerve fibers were observed in 4 / 7 mice receiving 80 IU / kg / day of insulin. These findings suggest that spontaneous peripheral neuropathy in aged mice is exacerbated by sustained hypoglycemia induced by insulin treatment.