Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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Lipid hydroperoxide-derived insulin resistance and its inhibition by pyridoxamine in skeletal muscle cells

  • Seon Hwa, Lee (Department of Bio-Analytical Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University) ;
  • Mizuki, Tsutsui (Department of Bio-Analytical Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University) ;
  • Atsushi, Matsunaga (Department of Bio-Analytical Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University) ;
  • Tomoyuki, Oe (Department of Bio-Analytical Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University)
  • Received : 2022.07.14
  • Accepted : 2022.11.15
  • Published : 2023.01.15
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Abstract

Oxidative stress is strongly associated with the onset and/or progression of diabetes. Under conditions of oxidative stress, lipid hydroperoxides are decomposed to reactive aldehydes that have been reported to induce insulin resistance by modifying proteins involved in insulin signaling. Pyridoxamine (PM) can inhibit the formation of advanced glycation/lipoxidation end products by scavenging reactive carbonyl species. Thus, PM has emerged as a promising drug candidate for various chronic conditions, including diabetic complications. In this study, L6 skeletal muscle cells were treated with 4-oxo-2(E)-nonenal (ONE), one of the most abundant and reactive lipid-derived aldehydes. Cellular insulin resistance was assessed by measuring insulin-stimulated glucose uptake using 2-deoxyglucose. ONE induced a time- and dose-dependent decrease in glucose uptake. Liquid chromatography/electrospray ionization-mass spectrometry analysis of the reaction between ONE and insulin receptor substrate 1 (IRS1) lysate identified multiple modifications that could disturb the interaction between IRS1 and activated IR, leading to insulin resistance. Pretreatment of the cells with PM restored the ONE-induced decrease in glucose uptake. Concomitantly, the formation of PM-ONE adducts in cell culture medium was increased in a PM-dose dependent manner. PM can therefore prevent lipid hydroperoxide-derived insulin resistance by quenching ONE.

Keywords

Acknowledgement

We are grateful to the Technical Support Center at Tohoku University for the use of their LTQ Orbitrap Velos.

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