Oligonol promotes glucose uptake by modulating the insulin signaling pathway in insulin-resistant HepG2 cells via inhibiting protein tyrosine phosphatase 1B

The high activity of the insulin-signaling pathway contributes to the enhanced feeding-induced stimulation of translation initiation in skeletal muscle of neonatal pigs. Protein-tyrosine-phosphatase 1B (PTP1B) is a negative regulator of the tyrosine phosphorylation of the insulin receptor (IR) and insulin receptor substrate 1 (IRS-1). The activity of PTP1B is determined mainly by its association with IR and Grb2. We examined the level of PTP1B activity, PTP1B protein abundance, PTP1B tyrosine phosphorylation, and the association of PTP1B with IR and Grb2 in skeletal muscle and liver of fasted and fed 7- and 26-day-old pigs. PTP1B activity in skeletal muscle was lower (P < 0.05) in 7- compared with 26-day-old pigs but in liver was similar in the two age groups. PTP1B abundances were similar in muscle but lower (P < 0.05) in liver of 7- compared with 26-day-old pigs. PTP1B tyrosine phosphorylation in muscle was lower (P < 0.05) in 7- than in 26-day-old pigs. The associations of PTP1B with IR and with Grb2 were lower (P < 0.05) at 7 than at 26 days of age in muscle, but there were no age effects in liver. Finally, in both age groups, fasting did not have any effect on these parameters. These results indicate that basal PTP1B activation is developmentally regulated in skeletal muscle of neonatal pigs, consistent with the developmental changes in the activation of the insulin-signaling pathway reported previously. Reduced PTP1B activation in neonatal muscle likely contributes to the enhanced insulin sensitivity of skeletal muscle in neonatal pigs.

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Glucose Uptake Stimulatory and PTP1B Inhibitory Activities of Pimarane Diterpenes from Orthosiphon stamineus Benth

Biomolecules ◽

10.3390/biom9120859 ◽

2019 ◽

Vol 9 (12) ◽

pp. 859 ◽

Cited By ~ 1

Author(s):

Phi Hung Nguyen ◽

Huynh Nhu Tuan ◽

Duc Thuan Hoang ◽

Quoc Trung Vu ◽

Minh Quan Pham ◽

...

Keyword(s):

Glucose Uptake ◽

Insulin Signaling ◽

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Protein Tyrosine Phosphatase 1B ◽

Protein Tyrosine ◽

Orthosiphon Stamineus ◽

Potent Inhibition ◽

Ic50 Values ◽

Inhibitory Activities

Seven pimarane diterpenes (1–7) were isolated from Orthosiphon stamineus Benth. by assay-guided isolation. All of the isolates possessed a 2-deoxy-2-((7-nitro-2,1,3-benzoxadiazol-4-yl)amino)-d-glucose uptake effect in 3T3-L1 adipocytes at concentrations of 5 and 10 μM. Most of them showed potent inhibition against protein tyrosine phosphatase 1B with IC50 values ranging from 0.33 to 9.84 μM. In the kinetic study, all inhibition types were exposed for the examined potencies, including mixed-competitive (1), non-competitives (3 and 5), competitive (6), and uncompetitive (7). The results suggested that O. stamineus and its pimarane diterpenes might exert the hypoglycemic effect via the insulin signaling pathway targeting inhibition of protein tyrosine phosphatase 1B (PTP1B) activity.

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Water Extract of Mungbean (Vigna radiata L.) Inhibits Protein Tyrosine Phosphatase-1B in Insulin-Resistant HepG2 Cells

Molecules ◽

10.3390/molecules26051452 ◽

2021 ◽

Vol 26 (5) ◽

pp. 1452

Author(s):

Orathai Saeting ◽

Kasemsiri Chandarajoti ◽

Angsuma Phongphisutthinan ◽

Parichat Hongsprabhas ◽

Sudathip Sae-tan

Keyword(s):

Glucose Metabolism ◽

Glucose Uptake ◽

Protein Tyrosine Phosphatase ◽

Hepg2 Cells ◽

Tyrosine Phosphatase ◽

Water Extract ◽

Protein Tyrosine ◽

Insulin Resistant ◽

Expression Of Genes ◽

Ptp 1B

The present study aimed to investigate the effects of mungbean water extract (MWE) on insulin downstream signaling in insulin-resistant HepG2 cells. Whole seed mungbean was extracted using boiling water, mimicking a traditional cooking method. Vitexin and isovitexin were identified in MWE. The results showed that MWE inhibited protein tyrosine phosphatase (PTP)-1B (IC50 = 10 μg/mL), a negative regulator of insulin signaling. MWE enhanced cellular glucose uptake and altered expression of genes involved in glucose metabolism, including forkhead box O1 (FOXO1), phosphoenolpyruvate carboxykinase (PEPCK), and glycogen synthase kinase (GSK)-3β in the insulin-resistant HepG2 cells. In addition, MWE inhibited both α-amylase (IC50 = 36.65 mg/mL) and α-glucosidase (IC50 = 3.07 mg/mL). MWE also inhibited the formation of advanced glycation end products (AGEs) (IC50 = 2.28 mg/mL). This is the first study to show that mungbean water extract increased cellular glucose uptake and improved insulin sensitivity of insulin-resistant HepG2 cells through PTP-1B inhibition and modulating the expression of genes related to glucose metabolism. This suggests that mungbean water extract has the potential to be a functional ingredient for diabetes.

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The key role of Akt protein kinase in metabolic-inflammatory pathways cross-talk: TNF-α down-regulation and improving of insulin resistance in HepG2 cell line

Current Molecular Medicine ◽

10.2174/1566524020666200427102209 ◽

2020 ◽

Vol 20 ◽

Author(s):

Iraj Alipourfard ◽

Salar Bakhtiyari ◽

Ali Gheysarzadeh ◽

Laura Di Renzo ◽

Antonio De Lorenzo ◽

...

Keyword(s):

Insulin Resistance ◽

Signaling Pathway ◽

Insulin Signaling ◽

Hepg2 Cells ◽

Insulin Signaling Pathway ◽

Target Cells ◽

Down Regulation ◽

Akt Phosphorylation ◽

Insulin Resistant ◽

Tnf Α

Background: Elevation of plasma free fatty acids as a principal aspect of type 2 diabetes maintains etiologically insulin insensitivity in target cells. TNF-α inhibitory effects on key insulin signaling pathway elements remain to be verified in insulin-resistant hepatic cells. Thus, TNF-α knockdown effects on the key elements of insulin signaling were investigated in the palmitate-induced insulin-resistant hepatocytes. The Akt serine kinase, a key protein of the insulin signaling pathway, phosphorylation was monitored to understand the TNF-α effect on probable enhancing of insulin resistance. Methods: Insulin-resistant HepG2 cells were produced using 0.5 mM palmitate treatment and shRNA-mediated TNF-α gene knockdown and its down-regulation confirmed using ELISA technique. Western blotting analysis used to assess the Akt protein phosphorylation status. Results: Palmitate-induced insulin resistance caused TNF-α protein overexpression 1.2-, 2.78, and 2.25- fold as compared to the control cells at post-treatment times of 8 h, 16 h, and 24 h, respectively. In the presence of palmitate, TNF-α expression showed around 30% reduction in TNF-α knockdown cells as compared to normal cells. In the TNF-α down-regulated cell, Akt phosphorylation was approximately 62% more than control cells after treatment with 100 nM insulin in conjugation with 0.5 mM palmitate. Conclusions: The obtained data demonstrated that TNF-α protein expression reduction improved insulin-stimulated Akt phosphorylation in the HepG2 cells and decreased lipid-induced insulin resistance of the diabetic hepatocytes.

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