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

Authors: Kou, ZZ  Li, CY  Tang, J  Hu, JC  Qu, J  Liao, YH  Wu, SX  Li, H  Li, YQ 
Citation: Kou ZZ, etal., Pain Physician. 2013 Mar-Apr;16(2):E71-83.
Pubmed: (View Article at PubMed) PMID:23511693

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.


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RGD Object Information
RGD ID: 10403050
Created: 2015-11-05
Species: All species
Last Modified: 2015-11-05
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.