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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.

SUBMITTER: Jiang H

PROVIDER: S-EPMC6389993 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Alisol A-24-acetate (AA-24-a) is one of the main active triterpenes isolated from the well-known medicinal plant Alisma orientale (Sam.) Juz., which possesses multiple biological activities, including a hypoglycemic effect. Whether AA-24-a is a hypoglycemic-active compound of A. orientale (Sam.) Juz. is unclear. The present study aimed to clarify the effect and potential mechanism of action of AA-24-a on glucose uptake in C2C12 myotubes. METHOD:Effects of AA-24-a on glucose uptake and GLUT4 translocation to the plasma membrane were evaluated. Glucose uptake was determined using a 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino)-2-deoxyglucose (2-NBDG) uptake assay. Cell membrane proteins were isolated and glucose transporter 4 (GLUT4) protein was detected by western blotting to examine the translocation of GLUT4 to the plasma membrane. To determine the underlying mechanism, the phosphorylation levels of proteins involved in the insulin and 5'-adenosine monophosphate-activated protein kinase (AMPK) pathways were examined using western blotting. Furthermore, specific inhibitors of key enzymes in AMPK signaling pathway were used to examine the role of these kinases in the AA-24-a-induced glucose uptake and GLUT4 translocation. RESULTS:We found that AA-24-a significantly promoted glucose uptake and GLUT4 translocation in C2C12 myotubes. AA-24-a increased the phosphorylation of AMPK, but had no effect on the insulin-dependent pathway involving insulin receptor substrate 1 (IRS1) and protein kinase B (PKB/AKT). In addition, the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and the AKT substrate of 160 kDa (AS160), two proteins that act downstream of AMPK, was upregulated. Compound C, an AMPK inhibitor, blocked AA-24-a-induced AMPK pathway activation and reversed AA-24-a-induced glucose uptake and GLUT4 translocation to the plasma membrane, indicating that AA-24-a promotes glucose metabolism via the AMPK pathway in vitro. STO-609, a calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ) inhibitor, also attenuated AA-24-a-induced glucose uptake and GLUT4 translocation. Moreover, STO-609 weakened AA-24-a-induced phosphorylation of AMPK, p38 MAPK and AS160. CONCLUSIONS:These results indicate that AA-24-a isolated from A. orientale (Sam.) Juz. significantly enhances glucose uptake via the CaMKKβ-AMPK-p38 MAPK/AS160 pathway.

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

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