Abstract
Aim: In this study, we investigated the relationship and molecular mechanisms between iron-overload and ER-stress-induced insulin resistance in human skeletal muscle cells. Methods: Intracellular iron was measured using calcein AM. Iron metabolism-related genes were analyzed by immunoblotting and PCR. The study was conducted using iron supplementation, which was achieved by palmitate, FeSO4 and FeCl3 administration, and iron reduction, which occurred by DFO, DS and Bapta AM administration, and knockdown of tfR1 or IRP2 genes, to investigate the effects of iron metabolism on insulin sensitivity in HSMMs. Intracellular calcium was detected using Fluo-3/AM staining. TfR1 internalization regulated by calcium was detected by GFP-labelled transferrin. Results: Endoplasmic reticulum stress by tunicamycin, thapsigargin, or palmitate evoked insulin resistance and simultaneously increased intracellular iron. Iron chelator, DFO, dramatically prevented ER-stress inducer-induced insulin resistance and iron donor impaired insulin sensitivity in vitro and in vivo through activation of JNK. Among several iron metabolism-related genes, tfR1 plays a predominant role for maintaining iron homeostasis in HSMMs. Treatment of ER-stress inducer positively regulated translocation of tfR1 by intracellular calcium, but protein levels of tfR1 did not change. Iron reduction, by adding iron chelator, calcium chelator, or knockdown of tfR1 or IRP2, dramatically prevented ER-stress-induced insulin resistance through the reduction of iron-overload. Conclusions/Interpretation: The current study shows ER-stress inducer evoked insulin resistance through iron overload. Reduction of intracellular iron, by iron chelator, significantly prevents insulin resistance. Therefore, attempts to block iron overload might be a strategy for preventing insulin resistance and diabetes. Disclosure K. Lee: None. R. Cui: None. D. Kim: None. S. Choi: None. W. Lee: None. Y. Kang: None. T. Kim: None. H. Moon: None. J. Jeon: None. S. Han: None. H. Kim: None.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
