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

2018 ◽  
Vol 62 (23) ◽  
pp. 1800709 ◽  
Author(s):  
Junhong Chen ◽  
Jing Sun ◽  
Richard A. Prinz ◽  
Yi Li ◽  
Xiulong Xu
Keyword(s):  
Insulin Receptor ◽  
Glucose Uptake ◽  
S6 Kinase ◽  
P70 S6 Kinase

scholarly journals Astaxanthin Inhibits p70 S6 Kinase 1 Activity to Sensitize Insulin Signaling

Marine Drugs ◽  
2020 ◽  
Vol 18 (10) ◽  
pp. 495
Author(s):  
Chunmei Li ◽  
Bixia Ma ◽  
Junhong Chen ◽  
Yoonhwa Jeong ◽  
Xiulong Xu
Keyword(s):  
Insulin Receptor ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Mechanisms Of Action ◽  
Serine Threonine Kinase ◽  
S6 Kinase ◽  
P70 S6 Kinase ◽  
L6 Myotubes ◽  
Ic50 Value

Astaxanthin (AST) is a carotenoid with therapeutic values on hyperglycemia and diabetic complications. The mechanisms of action of AST remain incompletely understood. p70 S6 kinase 1 (S6K1) is a serine/threonine kinase that phosphorylates insulin receptor substrate 1 (IRS-1)S1101 and desensitizes the insulin receptor (IR). Our present study aims to determine if AST improves glucose metabolisms by targeting S6K1. Western blot analysis revealed that AST inhibited the phosphorylation of two S6K1 substrates, S6S235/236 and IRS-1S1101, but enhanced the phosphorylation of AKTT308, AKTS473, and S6K1T389 by feedback activation of the phosphatidylinositol-3 (PI-3) kinase in 3T3-L1 adipocytes and L6 myotubes. In vitro kinase assays revealed that AST inhibited S6K1 activity with an IC50 value of approximately 13.8 μM. AST increased insulin-induced IR tyrosine phosphorylation and IRS-1 binding to the p85 subunit of PI-3 kinase. Confocal microscopy revealed that AST increased the translocation of the glucose transporter 4 (GLUT4) to the plasma membrane in L6 cells. Glucose uptake assays using a fluorescent dye, 2-NBDG (2-N-(Nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose), revealed that AST increased glucose uptake in 3T3-L1 adipocytes and L6 myotubes under insulin resistance conditions. Our study identifies S6K1 as a previously unrecognized molecular target of AST and provides novel insights into the mechanisms of action of AST on IR sensitization.

scholarly journals Ginsenoside Rb1 stimulates glucose uptake through insulin-like signaling pathway in 3T3-L1 adipocytes

2008 ◽  
Vol 198 (3) ◽  
pp. 561-569 ◽  
Author(s):  
Wenbin Shang ◽  
Ying Yang ◽  
Libin Zhou ◽  
Boren Jiang ◽  
Hua Jin ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Glucose Uptake ◽  
Signaling Pathway ◽  
Glucose Transport ◽  
Chinese Hamster Ovary Cells ◽  
Chinese Hamster ◽  
C2c12 Myotubes ◽  
Maximal Effect ◽  
Dependent Manner ◽  
Active Constituent

A series of clinical trials and animal experiments have demonstrated that ginseng and its major active constituent, ginsenosides, possess glucose-lowering action. In our previous study, ginsenoside Rb1 has been shown to regulate peroxisome proliferator-activated receptor γ activity to facilitate adipogenesis of 3T3-L1 cells. However, the effect of Rb1 on glucose transport in insulin-sensitive cells and its molecular mechanism need further elucidation. In this study, Rb1 significantly stimulated basal and insulin-mediated glucose uptake in a time- and dose-dependent manner in 3T3-L1 adipocytes and C2C12 myotubes; the maximal effect was achieved at a concentration of 1 μM and a time of 3 h. In adipocytes, Rb1 promoted GLUT1 and GLUT4 translocations to the cell surface, which was examined by analyzing their distribution in subcellular membrane fractions, and enhanced translocation of GLUT4 was confirmed using the transfection of GLUT4-green fluorescence protein in Chinese Hamster Ovary cells. Meanwhile, Rb1 increased the phosphorylation of insulin receptor substrate-1 and protein kinase B (PKB), and stimulated phosphatidylinositol 3-kinase (PI3K) activity in the absence of the activation of the insulin receptor. Rb1-induced glucose uptake as well as GLUT1 and GLUT4 translocations was inhibited by the PI3K inhibitor. These results suggest that ginsenoside Rb1 stimulates glucose transport in insulin-sensitive cells by promoting translocations of GLUT1 and GLUT4 by partially activating the insulin signaling pathway. These findings are useful in understanding the hypoglycemic and anti-diabetic properties of ginseng and ginsenosides.

Inhibition of p70 S6 kinase by rapamycin does not reverse the activated phenotype of pancreatic stellate cells

2001 ◽  
Vol 120 (5) ◽  
pp. A720
Author(s):  
Brent A. Neuschwander-Tetri ◽  
Lin Li ◽  
Lisa D. Wells ◽  
Bruce R. Bacon ◽  
Robert S. Britton
Keyword(s):  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
S6 Kinase ◽  
P70 S6 Kinase

Troglitazone acutely inhibits protein synthesis in endothelial cells via a novel mechanism involving protein phosphatase 2A-dependent p70 S6 kinase inhibition

2006 ◽  
Vol 291 (2) ◽  
pp. C317-C326 ◽  
Author(s):  
Du-Hyong Cho ◽  
Yoon Jung Choi ◽  
Sangmee Ahn Jo ◽  
Jungsang Ryou ◽  
Jin Yi Kim ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Protein Synthesis ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Peroxisome Proliferator ◽  
Inhibitory Effects ◽  
S6 Kinase ◽  
P70 S6 Kinase ◽  
Inhibition Of Protein Synthesis ◽  
Phosphatase 2A

Thiazolidinediones (TZDs), synthetic peroxisome proliferator-activated receptor γ (PPARγ) ligands, have been implicated in the inhibition of protein synthesis in a variety of cells, but the underlying mechanisms remain obscure. We report that troglitazone, the first TZD drug, acutely inhibited protein synthesis by decreasing p70 S6 kinase (p70S6K) activity in bovine aortic endothelial cells (BAEC). This inhibition was not accompanied by decreased phosphorylation status or in vitro kinase activity of mammalian target of rapamycin (mTOR). Furthermore, cotreatment with rapamycin, a specific mTOR inhibitor, and troglitazone additively inhibited both p70S6K activity and protein synthesis, suggesting that the inhibitory effects of troglitazone are not mediated by mTOR. Overexpression of the wild-type p70S6K gene significantly reversed the troglitazone-induced inhibition of protein synthesis, indicating an important role of p70S6K. Okadaic acid, a protein phosphatase 2A (PP2A) inhibitor, partially reversed the troglitazone-induced inhibition of p70S6K activity and protein synthesis. Although troglitazone did not alter total cellular PP2A activity, it increased the physical association between p70S6K and PP2A, suggesting an underlying molecular mechanism. GW9662, a PPARγ antagonist, did not alter any of the observed inhibitory effects. Finally, we also found that the mTOR-independent inhibitory mechanism of troglitazone holds for the TZDs ciglitazone, pioglitazone, and rosiglitazone, in BAEC and other types of endothelial cells tested. In conclusion, our data demonstrate for the first time that troglitazone (and perhaps other TZDs) acutely decreases p70S6K activity through a PP2A-dependent mechanism that is independent of mTOR and PPARγ, leading to the inhibition of protein synthesis in endothelial cells.

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