Quercetin and its metabolite isorhamnetin promote glucose uptake through different signalling pathways in myotubes

Abstract

Quercetin and its metabolite isorhamnetin elicit various beneficial effects on human health. However, their bioavailability is low. In this study, we investigated whether low concentrations in the physiological range could promote glucose uptake in L6 myotubes, as well as the underlying molecular mechanisms. We found that 0.1 nM and 1 nM quercetin or 1 nM isorhamnetin significantly increased glucose uptake via translocation of glucose transporter type 4 (GLUT4) to the plasma membrane of L6 myotubes. Quercetin principally activated the CaMKKβ/AMPK signalling pathway at these concentrations, but also activated IRS1/PI3K/Akt signalling at 10 nM. In contrast, 1 nM and 10 nM isorhamnetin principally activated the JAK/STAT pathway. Treatment with siAMPKα and siJAK2 abolished quercetin- and isorhamnetin-induced GLUT4 translocation, respectively. However, treatment with siJAK3 did not affect isorhamnetin-induced GLUT4 translocation, indicating that isorhamnetin induced GLUT4 translocation mainly through JAK2, but not JAK3, signalling. Thus, quercetin preferably activated the AMPK pathway and, accordingly, stimulated IRS1/PI3K/Akt signalling, while isorhamnetin activated the JAK2/STAT pathway. Furthermore, after oral administration of quercetin glycoside at 10 and 100 mg/kg body weight significantly induced GLUT4 translocation to the plasma membrane of skeletal muscles in mice. In the same animals, plasma concentrations of quercetin aglycone form were 4.95 and 6.80 nM, respectively. In conclusion, at low-concentration ranges, quercetin and isorhamnetin promote glucose uptake by increasing GLUT4 translocation via different signalling pathways in skeletal muscle cells; thus, these compounds may possess beneficial functions for maintaining glucose homeostasis by preventing hyperglycaemia at physiological concentrations.

Chlorogenic Acid Stimulates the Thermogenesis of Brown Adipocytes by Promoting the Uptake of Glucose and the Function of Mitochondria

“…In recent years, studies indicated that 1 µM propolis extract significantly promoted GLUT4 translocation and glucose uptake (Ueda, Hayashibara, & Ashida, ). The presence of 0.1 nM and 1 nM quercetin, or 1 nM isorhamnetin significantly increased glucose uptake by GLUT4 (Jiang, Yamashita, Nakamura, Croft, & Ashida, ). This study found that the insulin receptor substrate in the CGA‐treated group was not activated, and did not promote the expression of GLUT4.…”

Constitution of a comprehensive phytochemical profile and network pharmacology based investigation to decipher molecular mechanisms of Teucrium polium L. in the treatment of type 2 diabetes mellitus

“…Furthermore, glucose transporter 4 (GLUT4) induction through insulin-stimulated PI3K/AKT has an important role in whole-body glucose homeostasis by glucose intake at adipose tissue, cardiomyocytes and skeletal muscle cells ( Klip, McGraw & James, 2019 ). Previous reports on flavonoids like apigenin (TP5), quercetin (TP14), kaempferol showed enhancement in GLUT4 translocation ( Alkhalidy et al, 2015 ; Hossain et al, 2014 ; Jiang et al, 2019 ). According to the findings of our study, apigenin (TP5), luteolin (TP13), and quercetin (TP14) showed interaction with the target GLUT4 ( Table S5 ).…”

“…These findings indicated that insulin-like activity of T. polium is a result of increase in GLUT4 translocation ( Kadan et al, 2018 ). Quercetin (TP14) and gallic acid (TP16) increased glucose uptake through IRS1/PI3K/AKT signaling ( Gandhi et al, 2014 ; Jiang et al, 2019 ). Furthermore, it was shown that gallic acid and p -coumaric acid (TP17) ameliorate insulin shortage and insulin resistance ( Abdel-Moneim et al, 2018 ).…”

Peer Review #1 of "Constitution of a comprehensive phytochemical profile and network pharmacology based investigation to decipher molecular mechanisms of Teucrium polium L. in the treatment of type 2 diabetes mellitus (v0.1)"

“…Furthermore, glucose transporter 4 (GLUT4) induction through insulin-stimulated PI3K/AKT has an important role in whole-body glucose homeostasis by glucose intake at adipose tissue, cardiomyocytes and skeletal muscle cells (Klip et al 2019). Previous reports on flavonoids like apigenin (TP5), quercetin (TP14), kaempferol showed enhancement in GLUT4 translocation (Alkhalidy et al 2015;Hossain et al 2014;Jiang et al 2019). According to the findings of our study, apigenin (TP5), luteolin (TP13), and quercetin (TP14) showed interaction with the target GLUT4 (Table S5).…”

“…These findings indicated that insulin-like activity of T. polium is a result of increase in GLUT4 translocation (Kadan et al 2018). Quercetin (TP14) and gallic acid (TP16) increased glucose uptake through IRS1/PI3K/AKT signaling (Gandhi et al 2014;Jiang et al 2019). Furthermore, it was shown that gallic acid and p-coumaric acid (TP17) ameliorate insulin shortage and insulin resistance (Abdel-Moneim et al 2018).…”