title: Down-regulation of insulin signaling is involved in painful diabetic neuropathy in type 2 diabetes.
abstract: 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).
  
  
  OBJECTIVE
  Our aim was to explore insulin signaling to determine the molecular mechanism involved in the pathogenesis of PDN in T2DM.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Anatomy,The Fourth Military Medical University, Xi'an, China.
authors.forename: Zhen-Zhen
authors.initials: ZZ
authors.lastname: Kou
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Li
authors.forename: Jun
authors.initials: J
authors.lastname: Tang
authors.forename: Jia-Chen
authors.initials: JC
authors.lastname: Hu
authors.forename: Juan
authors.initials: J
authors.lastname: Qu
authors.forename: Yong-Hui
authors.initials: YH
authors.lastname: Liao
authors.forename: Sheng-Xi
authors.initials: SX
authors.lastname: Wu
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Yun-Qing
authors.initials: YQ
authors.lastname: Li
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism*; D003929:Diabetic Neuropathies / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism; D051379:Mice; D008820:Mice, Obese; D010146:Pain / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013116:Spinal Cord / Q000378:metabolism
chemical_list: D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D050796:STAT3 Transcription Factor; D011972:Receptor, Insulin; D053614:Janus Kinase 2