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 Control of hyperglycemia in male mice by leflunomide: mechanisms of action

2018 ◽  
Vol 237 (1) ◽  
pp. 43-58 ◽  
Author(s):  
Junhong Chen ◽  
Jing Sun ◽  
Michelle E Doscas ◽  
Jin Ye ◽  
Ashley J Williamson ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Glucose Transporter ◽  
Chow Diet ◽  
Serine Threonine Kinase ◽  
Glucose Levels ◽  
L6 Myotubes ◽  
Insulin Tolerance ◽  
Insulin Receptor Signaling ◽  
Normal Chow

p70 S6 kinase (S6K1) is a serine/threonine kinase that phosphorylates the insulin receptor substrate-1 (IRS-1) at serine 1101 and desensitizes insulin receptor signaling. S6K1 hyperactivation due to overnutrition leads to hyperglycemia and type 2 diabetes. Our recent study showed that A77 1726, the active metabolite of the anti-rheumatoid arthritis (RA) drug leflunomide, is an inhibitor of S6K1. Whether leflunomide can control hyperglycemia and sensitize the insulin receptor has not been tested. Here we report that A77 1726 increased AKTS473/T308 and S6K1T389 phosphorylation but decreased S6S235/236 and IRS-1S1101 phosphorylation in 3T3-L1 adipocytes, C2C12 and L6 myotubes. A77 1726 increased insulin receptor tyrosine phosphorylation and binding of the p85 subunit of the PI-3 kinase to IRS-1. A77 1726 enhanced insulin-stimulated glucose uptake in L6 myotubes and 3T3-L1 adipocytes, and enhanced insulin-stimulated glucose transporter type 4 (GLUT4) translocation to the plasma membrane of L6 cells. Finally, we investigated the anti-hyperglycemic effect of leflunomide on ob/ob and high-fat diet (HFD)-induced diabetes mouse models. Leflunomide treatment normalized blood glucose levels and overcame insulin resistance in glucose and insulin tolerance tests in ob/ob and HFD-fed mice but had no effect on mice fed a normal chow diet (NCD). Leflunomide treatment increased AKTS473/T308 phosphorylation in the fat and muscle of ob/ob mice but not in normal mice. Our results suggest that leflunomide sensitizes the insulin receptor by inhibiting S6K1 activity in vitro, and that leflunomide could be potentially useful for treating patients with both RA and diabetes.

Di(2-ethylhexyl)phthalate exposure impairs insulin receptor and glucose transporter 4 gene expression in L6 myotubes

2013 ◽  
Vol 33 (7) ◽  
pp. 685-700 ◽  
Author(s):  
P Rajesh ◽  
K Balasubramanian
Keyword(s):  
Gene Expression ◽  
Insulin Receptor ◽  
Glucose Uptake ◽  
Insulin Signaling ◽  
Glucose Transporter ◽  
Negative Influence ◽  
Receptor Protein ◽  
Dependent Manner ◽  
L6 Myotubes ◽  
Dose Dependent

Di(2-ethyl hexyl)-phthalate (DEHP) is an endocrine disrupter and is the most abundantly used phthalate derivative, which is suspected to be an inevitable environmental exposure contributing to the increasing incidence of type-2 diabetes in humans. Therefore, the present study was designed to address the dose-dependent effects of DEHP on insulin signaling molecules in L6 myotubes. L6 myotubes were exposed to different concentrations (25, 50, and 100 μM) of DEHP for 24 h. At the end of exposure, cells were utilized for assessing various parameters. Insulin receptor and glucose transporter4 (GLUT4) gene expression, insulin receptor protein concentration, glucose uptake and oxidation, and enzymatic and nonenzymatic antioxidants were significantly reduced, but glutamine fructose-6-phosphate amidotransferase, nitric oxide, lipid peroxidation, and reactive oxygen species levels were elevated in a dose-dependent manner in L6 myotubes exposed to DEHP. The present study in turn shows the direct adverse effect of DEHP on the expression of insulin receptor and GLUT4 gene, glucose uptake, and oxidation in L6 myotubes suggesting that DEHP exposure may have a negative influence on insulin signaling.

scholarly journals In vitro and in silico characterization of adiponectin-receptor agonist dipeptides

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Yuna Lee ◽  
Akihiro Nakano ◽  
Saya Nakamura ◽  
Kenta Sakai ◽  
Mitsuru Tanaka ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Glucose Transporter ◽  
Adenosine Monophosphate ◽  
Adiponectin Receptor ◽  
L6 Myotubes ◽  
Glut4 Expression ◽  
Binding Pockets ◽  
Dynamics Simulations ◽  
In Silico Characterization

AbstractThe aim of this study is to develop a dipeptide showing an adiponectin receptor 1 (AdipoR1) agonistic effect in skeletal muscle L6 myotubes. Based on the structure of the AdipoR1 agonist, AdipoRon, 15 synthetic dipeptides were targeted to promote glucose uptake in L6 myotubes. Tyr-Pro showed a significant increase in glucose uptake among the dipeptides, while other dipeptides, including Pro-Tyr, failed to exert this effect. Tyr-Pro induces glucose transporter 4 (Glut4) expression in the plasma membrane, along with adenosine monophosphate-activated protein kinase (AMPK) activation. In AdipoR1-knocked down cells, the promotion by Tyr-Pro was ameliorated, indicating that Tyr-Pro may directly interact with AdipoR1 as an agonist, followed by the activation of AMPK/Glut4 translocation in L6 myotubes. Molecular dynamics simulations revealed that a Tyr-Pro molecule was stably positioned in the two potential binding pockets (sites 1 and 2) of the seven-transmembrane receptor, AdipoR1, anchored in a virtual 1-palmitoyl-2-oleoyl-phosphatidylcholine membrane. In conclusion, we demonstrated the antidiabetic function of the Tyr-Pro dipeptide as a possible AdipoR1 agonist.

Comparative effects of IGF-I and insulin on the glucose transporter system in rat muscle

1994 ◽  
Vol 267 (3) ◽  
pp. E461-E466 ◽  
Author(s):  
S. Lund ◽  
A. Flyvbjerg ◽  
G. D. Holman ◽  
F. S. Larsen ◽  
O. Pedersen ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Acute Effect ◽  
Maximal Effect ◽  
Dependent Manner ◽  
Glut 4 ◽  
Igf I ◽  
Glut 4 Translocation

The acute effect of insulin-like growth factor I (IGF-I) and insulin on glucose uptake and the glucose transport system in in vitro incubated rat soleus muscles was examined using 3-O-methylglucose and the ATB-[3H]BMPA exofacial photolabeling technique. IGF-I and insulin both stimulated 3-O-methylglucose uptake and GLUT-4 translocation in a dose-dependent manner with a maximal effect six- to sevenfold above basal. No additive effects of IGF-I and insulin on maximal 3-O-methylglucose uptake were found. On a molar basis, IGF-I was 13 times less potent than insulin. Receptor binding experiments showed that IGF-I exhibited a much lower affinity for the insulin receptor [half-maximal effective dose (ED50) = 28.5 nM] than that of insulin (ED50 = 0.20 nM). In contrast, IGF-I bound to the partially purified IGF-I receptor with an apparent affinity (ED50 = 3.7 nM) that was similar to the concentrations of IGF-I which caused half-maximal activation of 3-O-methylglucose uptake (ED50 = 2.4 nM) and GLUT-4 translocation (ED50 = 2.5 nM). Our findings suggest that IGF-I exerts its insulin-like effects on glucose uptake primarily through its own specific receptor and that the molecular events underlying IGF-I and insulin actions on glucose uptake in skeletal muscle are similar, namely caused by a translocation of the GLUT-4 transporter from an intracellular pool to the cell surface.

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

In vitro glucose uptake activity of Aegles marmelos and Syzygium cumini by activation of Glut-4, PI3 kinase and PPARγ in L6 myotubes

Phytomedicine ◽  
2006 ◽  
Vol 13 (6) ◽  
pp. 434-441 ◽  
Author(s):  
R. Anandharajan ◽  
S. Jaiganesh ◽  
N.P. Shankernarayanan ◽  
R.A. Viswakarma ◽  
A. Balakrishnan
Keyword(s):  
Glucose Uptake ◽  
Pi3 Kinase ◽  
Syzygium Cumini ◽  
Glut 4 ◽  
L6 Myotubes ◽  
Uptake Activity

scholarly journals Antihyperglycemic and Antilipidemic Effects of the Ethanol Extract Mixture of Ligularia fischeri and Momordica charantia in Type II Diabetes-Mimicking Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-15
Author(s):  
Hyun Jin Baek ◽  
Yong Joon Jeong ◽  
Jeong Eun Kwon ◽  
Jong Sung Ra ◽  
Sung Ryul Lee ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Uptake Rate ◽  
Glucose Transporter ◽  
Synergistic Effects ◽  
Momordica Charantia ◽  
C2c12 Cells ◽  
Peroxisome Proliferator ◽  
Glucose Uptake Rate ◽  
Ligularia Fischeri

The extract of the Momordica charantia fruit (MCE) is recognized as an alternative treatment for diabetes. The extract of Ligularia fischeri leaves (LFE) is traditionally used as a folk medicine for treating inflammatory diseases in Korea as well. In this study, we investigated the synergistic effect of MCE combined with LFE on antihyperglycemic and antihyperlipidemic potentials. Based on the α-glucosidase inhibitory effect and promotion of adipocyte differentiation in the 3T3-L1 cell line, the MLM was prepared with MCE:LFE (8:2 weight:weight). MLM showed the synergistic effects in the promotion of the glucose uptake rate, suppression of dipeptidyl peptidase-4 (DPP-4) mRNA expression, upregulation of an insulin receptor substrate and glucose transporter type-4 expression, and an increase in insulin-associated signaling in C2C12 cells. In addition, the efficacy of peroxisome proliferator-activated receptor-γ agonism and glucose uptake rate by MLM supplementation was significantly enhanced in vitro. Then, the antihyperglycemic and antihyperlipidemic effects of MCE, LFE, and MLM at the dose of 50, 100, and 200 mg/kg/day (n = 6 per each group) were determined in streptozotocin (STZ)-insulted mice fed an atherogenic diet (ATH) for 4 weeks. In addition, MLM (50, 100, and 200 mg/kg/day, n = 5 per each group) was supplemented in ATH-fed db/db mice for 10 weeks. Compared with MCE or LFE alone, MLM supplementation led to a more significant reduction of glucose levels in both STZ/ATH and db/db/ATH mice as well as lowered lipid profiles in STZ/ATH mice. In addition, the stimulation of islet of Langerhans regeneration was more pronounced by MLM supplementation in both mice models. In conclusion, antihyperglycemic and antihyperlipidemic effects were strengthened by the combined extracts of L. fischeri and M. charantia (MLM) in diabetes-mimicking mice.

scholarly journals Transient Silencing of a Type IV P-Type ATPase,Atp10c, Results in Decreased Glucose Uptake in C2C12 Myotubes

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
S. E. Hurst ◽  
S. C. Minkin ◽  
J. Biggerstaff ◽  
M. S. Dhar
Keyword(s):  
Type 2 Diabetes ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Mapk Pathway ◽  
Specific Inhibitor ◽  
C2c12 Myotubes ◽  
Glucose Transporter 1 ◽  
Transfected Cells

Atp10cis a strong candidate gene for diet-induced obesity and type 2 diabetes. To identify molecular and cellular targets of ATP10C,Atp10cexpression was alteredin vitroin C2C12 skeletal muscle myotubes by transient transfection with anAtp10c-specific siRNA. Glucose uptake assays revealed that insulin stimulation caused a significant 2.54-fold decrease in 2-deoxyglucose uptake in transfected cells coupled with a significant upregulation of native mitogen-activated protein kinases (MAPKs), p38, and p44/42. Additionally, glucose transporter-1 (GLUT1) was significantly upregulated; no changes in glucose transporter-4 (GLUT4) expression were observed. The involvement of MAPKs was confirmed using the specific inhibitor SB203580, which downregulated the expression of native and phosphorylated MAPK proteins in transfected cells without any changes in insulin-stimulated glucose uptake. Results indicate thatAtp10cregulates glucose metabolism, at least in part via the MAPK pathway, and, thus, plays a significant role in the development of insulin resistance and type 2 diabetes.

scholarly journals Specific activation of p85-p110 phosphatidylinositol 3'-kinase stimulates DNA synthesis by ras- and p70 S6 kinase-dependent pathways.

1997 ◽  
Vol 17 (1) ◽  
pp. 248-255 ◽  
Author(s):  
J McIlroy ◽  
D Chen ◽  
C Wjasow ◽  
T Michaeli ◽  
J M Backer
Keyword(s):  
Dna Synthesis ◽  
Affinity Purification ◽  
Specific Inhibitor ◽  
Brdu Incorporation ◽  
Glutathione S Transferase ◽  
Intact Cells ◽  
S6 Kinase ◽  
P70 S6 Kinase ◽  
Quiescent Cells

We have developed a polyclonal antibody that activates the heterodimeric p85-p110 phosphatidylinositol (PI) 3'-kinase in vitro and in microinjected cells. Affinity purification revealed that the activating antibody recognized the N-terminal SH2 (NSH2) domain of p85, and the antibody increased the catalytic activity of recombinant p85-p110 dimers threefold in vitro. To study the role of endogenous PI 3'-kinase in intact cells, the activating anti-NSH2 antibody was microinjected into GRC + LR73 cells, a CHO cell derivative selected for tight quiescence during serum withdrawal. Microinjection of anti-NSH2 antibodies increased bromodeoxyuridine (BrdU) incorporation fivefold in quiescent cells and enhanced the response to serum. These data reflect a specific activation of PI 3'-kinase, as the effect was blocked by coinjection of the appropriate antigen (glutathione S-transferase-NSH2 domains from p85 alpha), coinjection of inhibitory anti-p110 antibodies, or treatment of cells with wortmannin. We used the activating antibodies to study signals downstream from PI 3'-kinase. Although treatment of cells with 50 nM rapamycin only partially decreased anti-NSH2-stimulated BrdU incorporation, coinjection with an anti-p70 S6 kinase antibody effectively blocked anti-NSH2-stimulated DNA synthesis. We also found that coinjection of inhibitory anti-ras antibodies blocked both serum- and anti-NSH2-stimulated BrdU incorporation by approximately 60%, and treatment of cells with a specific inhibitor of MEK abolished antibody-stimulated BrdU incorporation. We conclude that selective activation of physiological levels of PI 3'-kinase is sufficient to stimulate DNA synthesis in quiescent cells. PI 3'-kinase-mediated DNA synthesis requires both p70 S6 kinase and the P21ras/MEK pathway.

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