Down-regulation of insulin signaling is involved in painful diabetic neuropathy in type 2 diabetes

Background: previous theories considered that the main cause of painful diabetic neuropathy (pdn) was due to hyperglycemia. however,recent evidence indicated that hyperinsulinemia plays a greater role in type 2 diabetic metabolisms (t2dm). objectives: our aim was to explore insulin signaling to determine the molecular mechanism involved in the pathogenesis of pdn in t2dm. study design: a randomized,double blind,controlled animal trial. methods: we observed the localization of insulin receptor (ir) and phosphorylated insulin receptor substrate 1 (irs-1) in the spinal cord using in situ hybridization and immunohistochemistry. then we investigated the alternations of ir and pirs-1 and the activity of the jak2/stat3 pathway by immunohistochemistry,western blotting,and cell culture. finally,we detected the influence of intrathecal jak2/stat3 inhibitor (ag490) on nociceptive behavior and insulin signaling in ob/ob mice using western blotting. results: we found that ir and pirs-1 are mainly located in neurons in the superficial layer of the spinal dorsal horn. the expressions of ir and pirs-1 decreased and the jak2/stat3 pathway activated in the spinal dorsal horn in ob/ob mice with mechanical hyperalgesia. next,our in vitro results indicated that hyperinsulinemia and hyperglycemia impaired insulin signaling along with the activated jak2/stat3 pathway in differentiated human neuronal cells (sh-sy5y). treatment through intrathecal injection of ag490,an inhibitor of the jak2/stat3 pathway,alleviated mechanical hyperalgesia in ob/ob mice and prevented impaired insulin signaling in the spinal cord. limitations: the activation of the jak2/stat3 pathway could not explain the mechanism of pdn in t1dm. conclusions: we demonstrate that insulin signaling impairment in the spinal dorsal horn is associated with the activated jak2/stat3 pathway,which contributes to the progressive pdn in t2dm.