Document Detail

Inhibitory Cross-talk between the AMPK and ERK pathways mediates endoplasmic reticulum stress-induced insulin resistance in skeletal muscle.
MedLine Citation:
PMID:  23373714     Owner:  NLM     Status:  Publisher    
BACKGROUND AND PURPOSE: ER stress has been implicated in the pathogeneses of insulin resistance and type 2 diabetes, and extracellular signal-regulated kinase (ERK) antagonist is an insulin sensitizer that can restore muscle insulin responsiveness in both tunicamycin-treated muscle cells and type 2 diabetic mice. The present study was undertaken to determine whether the chemical or genetic inhibition ER stress pathway targeting by ERK results in metabolic benefits in muscle cells. EXPERIMENTAL APPROACH: ER stress was induced in L6 myotubes using tunicamycin (5 μg/ml) or thapsigargin (300 nM), and cells were transfected with siRNA ERK or AMPKα2. Changes in ER stress and in the ERK and AMPK signaling pathways were explored by Western blotting. The phosphorylation levels of insulin receptor substrate 1(IRS-1) were analyzed by Immunoprecipitation and using a glucose uptake assay. KEY RESULTS: ER stress dampened insulin-stimulated signals and glucose uptake, whereas treatment with the specific ERK inhibitor U0126 (25 μM) rescued impaired insulin signaling via AMPK activation. In db/db mice, U0126 administration decreased markers of insulin resistance and increased the phosphorylations of Akt and AMPK in muscle tissues. CONCLUSIONS AND IMPLICATIONS: Inhibition of ERK signaling pathways by a chemical inhibitor and knockdown of ERK improved AMPK and Akt signalings and reversed ER stress-induced insulin resistance in L6 myotubes. These findings suggest that ERK signaling plays an important role in the regulation of insulin signals in muscle cells under ER stress.
Seung-Lark Hwang; Yong-Tae Jeong; Xian Li; Yong Deuk Kim; Lu Yue; Young-Chae Chang; In-Kyu Lee; Hyeun Wook Chang
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-2-4
Journal Detail:
Title:  British journal of pharmacology     Volume:  -     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-2-4     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
© 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society.
College of Pharmacy, Yeungnam University, Gyeongsan, 712-749, Republic of Korea; Department of Internal Medicine, Research Institute of Aging and Metabolism, WCU Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
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