Dexmedetomidine alleviates insulin resistance in hepatocytes by reducing endoplasmic reticulum stress

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.

The role of Smad4 in the regulation of insulin resistance, inflammation and cell proliferation in HTR8‐Svneo cells

“…As previously studied, IR is universally acknowledged as a dysfunctional glucose uptake caused by the abnormality in which certain amount of insulin exerts a much lower biological effect than expected 6 . Several methods have been demonstrated to induce the insulin resistance, including high fat diet, 19 high insulin 20 and even dexamethasone 21 . In our study, HTR‐8/SVneo cells were incubated with 10 −6 M insulin for 48 hours to build a cellular model of IR.…”

Propofol Improved Glucose Tolerance Associated with Increased FGF-21 and GLP-1 Production in Male Sprague-Dawley Rats

“…GLP-1 production from enteroendocrine L cells is stimulated by food ingestion, and its stability is regulated by dipeptidyl peptidase IV (DPP-IV). The released GLP-1 induces glucose-stimulated insulin secretion, inhibits glucagon secretion, and protects pancreatic β-cells via GLP-1R [ 31 ]. Additionally, GLP-1 is also a stimulator of hepatic FGF-21 expression [ 17 ].…”

Metabolic Syndrome and Psoriasis: Mechanisms and Future Directions

“…Treatment with the ER stress inhibitor (tauroursodeoxycholate) can improve metabolic parameters in MetS rat and mitigate the MetS-induced cardiovascular complications (101). Reducing ER stress can alleviate IR (102)(103)(104)(105). Specifically, the interfered transport of newly synthesized insulin proreceptors from ER to the plasma membrane can inhibit the proteolytic maturation of insulin proreceptors.…”