Quercetin But Not Quercitrin Ameliorates Tumor Necrosis Factor-Alpha-Induced Insulin Resistance in C2C12 Skeletal Muscle Cells

Abstract

Skeletal muscle is a major site for glucose metabolism and its injury by cytokines can induce insulin resistance leading to type 2 diabetes. It has been suggested that quercetin may act as an anti-diabetic agent, however, the effects of quercetin on insulin resistance in skeletal muscle remain unknown. We aimed to investigate the role of quercetin and its glycoside, quercitrin in tumor necrosis factor-alpha (TNF-α) induced C2C12 skeletal muscle cell impairment. Quercetin, but not quercitrin moderately attenuated the effects of TNF-α and enhanced the basal and insulin stimulated uptake of glucose in a dose-dependent manner via the activation of the protein kinase B (Akt) and AMP-activated protein kinase (AMPK) pathways. Furthermore, the underlying mechanism also involved the suppression of nuclear factor-κB (NF-κB) signaling and the nitric oxide (NO)/inducible nitric oxide synthase (iNOS) system, downstream of AMPK transduction. In summary, quercetin exhibited its effect of improving glucose uptake and insulin sensitivity in skeletal muscle cells via the two independent signaling pathways of Akt and AMPK, and can be developed as a potential anti-diabetic agent.Key words skeletal muscle cell; insulin resistance; quercetin; inflammation; AMP-activated protein kinase Type 2 diabetes is characterized by low-grade systemic inflammation, 1) and elevated levels of circulating proinflammatory mediators may lead to the process of insulin resistance, a critical issue for understanding the mechanisms that contribute to type 2 diabetes.2,3) Cytokines like tumor necrosis factor-alpha (TNF-α) directly bind to their receptor(s) on muscle cells or hepatocytes, interfere with intracellular insulin signaling by converging on common signaling routes like the nuclear factor-κB (NF-κB) pathway, and eventually dampen the cellular response to insulin. [3][4][5] Skeletal muscle is recognized as the major tissue for glucose metabolism, taking up nearly three quarters of insulin stimulated glucose uptake in the entire body.6) There are at least two major mechanisms for the uptake of glucose by glucose transporter 4 (Glut4) in skeletal muscle: one is an insulin-dependent phosphoinositide 3 (PI3) kinase and protein kinase B (Akt) pathway, while the other is an AMP-activated protein kinase (AMPK) signaling pathway stimulated by metabolic stress. 7,8) The serine/threonine kinase Akt, also known as protein kinase B (PKB) is a pivotal node in cell signaling downstream of growth factors, cytokines and other stimuli. 9)Cytokines may also affect insulin independent pathways regulating glucose disposal such as inhibiting the activation of AMPK.10) AMPK is a fuel-sensing enzyme, the phosphorylation of which regulates glucose uptake. 11) However, its role in skeletal muscle remains unclear. 12,13)Dietary compounds with anti-inflammatory properties that affect insulin sensitivity may be promising candidates for manipulating skeletal muscle insulin resistance for their low side effects and readily available natural sources. Quercetin (3,5,7,3′,4′-penta...

Combretum lanceolatum flowers ethanol extract inhibits hepatic gluconeogenesis: an in vivo mechanism study

“…Taken together, these data suggested that ClEtOH probably has compounds that, isolated or combination, present an insulin-like action, stimulating insulinsignalling intermediates. Corroborating our hypothesis, Dai et al (2013) attributed the antidiabetic effect of quercetin to its ability to stimulate AKT (and also AMPK) in skeletal muscle cells, leading to an increased glucose uptake. Finally, the stimulation of hepatic AKT could explain not only the decrease in the PEPCK levels and in gluconeogenesis but also the increase in the hepatic glycogen content previously observed in diabetic rats treated with ClEtOH (Dechandt et al 2013); the stimulation of liver glycogen synthesis could be an additional mechanism of the extract that also contributes to reduce hyperglycaemia.…”

Adenosine Monophosphate (AMP)-Activated Protein Kinase: A New Target for Nutraceutical Compounds

“…In addition to this, quercetin treatments resulted in interesting effects, improving insulin sensitivity in muscle cells through the AMPK pathway, which is involved in cellular glucose uptake by glucose transporter type 4. These findings suggest that quercetin constitutes a nutraceutical compound able to ameliorate insulin resistance in muscle cells through different events linked to AMPK phosphorylation and activation [87]. Phenolic alcohols, such as hydroxytyroxol (Table 3) were also found to increase fatty acid oxidation and to improve insulin sensitivity through AMPK phosphorylation, as shown in 3T3-L1 adipocytes, suggesting its possible involvement in diabetes mellitus management [88].…”

Quercetin alleviates cell apoptosis and inflammation via the ER stress pathway in vascular endothelial cells cultured in high concentrations of glucosamine

“…Furthermore, quercetin alleviates AS development in rabbits (30) and mice (31). Quercetin has also been demonstrated to control blood glucose levels, and improve glucose uptake and insulin sensitivity in vitro (32,33). Suganya et al (34) also demonstrated that quercetin prevents tunicamycin-induced ER stress through modulation of GRP78 and CHOP levels in endothelial cells.…”