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Lipid hydroperoxide-derived insulin resistance and its inhibition by pyridoxamine in skeletal muscle cells

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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.

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Acknowledgements

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

Funding

This work was supported in part by a Grants-in-Aid for Scientific Research (C) (to S.H.L., 19K07187 for 2019−2021) and for Scientific Research (B) (to T.O., 16H05078 for 2016–2018) from the Japan Society for the Promotion of Science (JSPS).

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  1. Department of Bio-Analytical Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan

    Seon Hwa Lee, Mizuki Tsutsui, Atsushi Matsunaga & Tomoyuki Oe

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Correspondence to Seon Hwa Lee or Tomoyuki Oe.

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Lee, S.H., Tsutsui, M., Matsunaga, A. et al. Lipid hydroperoxide-derived insulin resistance and its inhibition by pyridoxamine in skeletal muscle cells. Toxicol Res. 39, 147–156 (2023). https://doi.org/10.1007/s43188-022-00155-z

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  • DOI: https://doi.org/10.1007/s43188-022-00155-z

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