Dexmedetomidine alleviates insulin resistance in hepatocytes by reducing endoplasmic reticulum stress
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ORIGINAL ARTICLE
Dexmedetomidine alleviates insulin resistance in hepatocytes by reducing endoplasmic reticulum stress Fanfan Liu1 Shaojun Zhu1 Lifeng Ni1 Ling’er Huang1 Kuirong Wang1 Yanfeng Zhou ●
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Received: 5 July 2019 / Accepted: 16 October 2019 © The Author(s) 2019
Abstract Purpose Dexmedetomidine (DEX) stabilizes intraoperative blood glucose levels and reduces insulin resistance (IR), a common perioperative complication. However, the molecular mechanisms underlying these effects remain unclear. Since endoplasmic reticulum stress (ERS) is a mechanism of IR, this study sought to examine whether DEX can effectively alleviate IR by reducing ERS. Methods HepG2 and LO2 cells were treated with different concentrations of insulin. The glucose content assay and Cell Counting Kit-8 (CCK-8) were then employed to determine the optimal insulin concentration capable of inducing IR without affecting cell viability. Insulin-resistant hepatocytes were cultured with different concentrations of DEX for 24 h, and the glucose concentration in the supernatant was measured. ERS was assessed by qPCR and western blotting. The latter was also used to quantify the expression of phosphorylated protein kinase B (p-AKT), phosphoenolpyruvate carboxykinase (PEPCK), and glucose 6 phosphatase (G6Pase), which are key proteins involved in the action of insulin. Results After 48-h of culturing with 10 μg/mL insulin, glucose consumption in hepatocytes was found to be reduced. IR hepatocytes cultured with 10, 100, or 1000 ng/ml DEX for 24 h showed a concentration-dependent increase in glucose consumption. Elevated mRNA and protein levels of ERS markers binding immunoglobulin protein (BIP) and ER protein 29 (ERp29), were reversed by DEX treatment. Moreover, reduced p-AKT and increased PEPCK and G6Pase protein levels in IR hepatocytes were also restored following DEX treatment. Conclusion DEX may alleviate IR in hepatocytes by reducing ERS serving to restore insulin action via the IRS-1/PI3K/AKT pathway. Keywords Dexmedetomidine Insulin resistance Endoplasmic reticulum stress Hepatocytes AKT ●
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Introduction Insulin resistance (IR) results from impaired glucose metabolism, and is characterized by a decreased sensitivity of target organs to insulin. IR is one of the most common and serious perioperative complications and is frequently associated with a longer hospital stay, increased susceptibility to infection, and higher risk of mortality [1–3].
These authors contributed equally: Fanfan Liu, Shaojun Zhu * Yanfeng Zhou [email protected] 1
Department of Anesthesiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China
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The liver plays an important role in glucose metabolism, although adipose tissue and skeletal muscle are also targeted by insulin. IR in the liver can lead to increased gluconeogenesis and glycogen output, resulting in fasting hyperglycemia and hyperinsulinemia. On the other hand, fat mobilization and fatty acid oxidation a
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