• Zhen-Zhen Kou, Chun-Yu Li, Jun Tang, Jia-Chen Hu, Juan Qu, Yong-Hui Liao, Sheng-Xi Wu, Hui Li, and Yun-Qing Li.
• Department of Anatomy,The Fourth Military Medical University, Xi'an, China.
• Pain Physician. 2013 Mar 1;16(2):E71-83.

BackgroundPrevious 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).ObjectivesOur aim was to explore insulin signaling to determine the molecular mechanism involved in the pathogenesis of PDN in T2DM.Study DesignA randomized, double blind, controlled animal trial.MethodsWe 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.ResultsWe 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.LimitationsThe activation of the JAK2/STAT3 pathway could not explain the mechanism of PDN in T1DM.  ConclusionsWe 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.

35 keywords...

hide…