Gingerenone A Sensitizes the Insulin Receptor and Increases Glucose Uptake by Inhibiting the Activity of p70 S6 Kinase

Abstract

Scope: The bioactive constituents in ginger extract responsible for their anti-hyperglycemic effect and the underlying mechanisms are incompletely understood. Gingerenone A (Gin A) has been identified as an inhibitor of p70 S6 (S6K1), a kinase that plays a critical role in the pathogenesis of insulin resistance. Our study aims to evaluate if Gin A can sensitizes the insulin receptor by inhibiting S6K1 activity. Methods and results: Western blot analysis revealed that Gin A induced phosphatidylinositide-3 kinase (PI3K) feedback activation in murine 3T3-L1 adipocytes and rat L6 myotubes, as evidenced by increased AKTS473 and S6K1T389 but decreased S6S235/236 and insulin receptor substrate 1 (IRS-1)S1101 phosphorylation. Western blot and immunoprecipitation analysis revealed that Gin A increased insulin receptor tyrosine phosphorylation in L6 myotubes and IRS-1 binding to the PI3K in 3T3-L1 adipocytes. Confocal microscopy revealed that Gin A enhanced insulin-induced translocation of glucose transporter 4 (GLUT4) into the cell membrane in L6 cells. 2-NBDG(2-N-(Nitrobenz-2-oxa-1,3-diazol-4-yl)amino)−2-deoxyglucose) fluorescent assay revealed that Gin A enhanced insulin-stimulated glucose uptake in 3T3-L1 adipocytes and L6 myotubes. Conclusions: Gin A overcomes insulin resistance and increases glucose uptake by inhibiting S6K1 activity. Gin A or other plant-derived S6K1 inhibitors could be developed as novel anti-diabetic agents.

Astaxanthin Inhibits p70 S6 Kinase 1 Activity to Sensitize Insulin Signaling

“…IRS-1 is a crucial adaptor protein that is phosphorylated at multiple serine and threonine residues by several kinases involved in insulin resistance [ 9 , 12 ]. IRS-1 S1101 phosphorylation by S6K1 leads to its weak binding to the p85 subunit of PI-3 kinase and poor activation [ 16 , 42 ]. In addition, IRS-1 S1101 phosphorylation also accelerates its degradation [ 43 ].…”

“…In addition, IRS-1 S1101 phosphorylation also accelerates its degradation [ 43 ]. Chen et al reported that A77 1726 and gingerenone A, two S6K1 inhibitors, inhibit IRS-1 S1101 phosphorylation, sensitize the IR, and increase glucose uptake [ 16 , 44 ]. Ishiki et al [ 30 ] reported that AST treatment of L6 myotubes leads to decreased phosphorylation of IRS-1 at serine 307, a site that is phosphorylated by c-Jun terminal kinase (JNK) [ 45 ].…”

“…It is well established that inhibition of S6K1 activity leads to feedback activation of the PI-3 kinase pathway and improved insulin signaling [ 9 , 12 ]. We recently reported that inhibition of S6K1 activity by A77 1726 and gingerenone A leads to increased AKT phosphorylation in 3T3-L1 adipocytes and L6 myotubes under normal and insulin-resistant conditions [ 16 , 44 ]. Several prior studies have shown that AST enhances AKT phosphorylation in L6 myotubes [ 30 ] and SH-SY5Y cells, a neuroblastoma cell line [ 31 , 50 ].…”

“…S6K1 inhibitors have been increasingly recognized as potential anti-diabetic drugs for treating T2DM. Several S6K1 inhibitors, such as PF-4708671, leflunomide, and gingerenone A, control hyperglycemia by sensitizing the IR and enhancing glucose uptake [ 16 , 40 , 44 ]. Leflunomide, a clinically approved anti-rheumatoid arthritis (RA) drug, has exhibited anti-hyperglycemic effects in RA patients [ 53 , 54 ].…”

“…mTOR phosphorylates and activates S6K1, which then phosphorylates IRS-1 S1101 , leading to poor activation of its downstream PI-3 kinase as evidenced by weak binding of the PI-3 kinase to IRS-1 and weak AKT phosphorylation upon insulin stimulation [ 9 , 10 ]. Several natural products such as gingerenone A and evodiamine, which inhibit S6K1 activity, can increase glucose uptake or improve glucose tolerance [ 15 , 16 ].…”