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KMID : 0043320170400111314
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Archives of Pharmacal Research
2017 Volume.40 No. 11 p.1314 ~ p.1327
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Oligonol promotes glucose uptake by modulating the insulin signaling pathway in insulin-resistant HepG2 cells via inhibiting protein tyrosine phosphatase 1B
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Bhakta Himanshu Kumar
Paudel Pradeep
Fujii Hajime
Sato Atsuya
Park Chan-Hum
Yokozawa Takako
Jung Hyun-Ah
Choi Jae-Sue
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Abstract
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Insulin resistance and protein tyrosine phosphatase 1B (PTP1B) overexpression are strongly associated with type 2 diabetes mellitus (T2DM), which is characterized by defects in insulin signaling and glucose intolerance. In a previous study, we demonstrated oligonol inhibits PTP1B and α-glucosidase related to T2DM. In this study, we examined the molecular mechanisms underlying the anti-diabetic effects of oligonol in insulin-resistant HepG2 cells. Glucose uptake was assessed using a fluorescent glucose tracer, 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose, and the signaling pathway was investigated by western blotting. Oligonol significantly increased insulin-provoked glucose uptake and decreased PTP1B expression, followed by modulation of ERK phosphorylation. In addition, oligonol activated insulin receptor substrate 1 by reducing phosphorylation at serine 307 and increasing that at tyrosine 895, and enhanced the phosphorylations of Akt and phosphatidylinositol 3-kinase. Interestingly, it also reduced the expression of two key enzymes of gluconeogenesis (glucose 6-phosphatase and phosphoenolpyruvate carboxykinase), attenuated oxidative stress by scavenging/inhibiting peroxynitrite, and reactive oxygen species (ROS) generation, and augmented the expression of nuclear factor kappa B. These findings suggest oligonol improved the insulin sensitivity of insulin-resistant HepG2 cells by attenuating the insulin signaling blockade and modulating glucose uptake and production. Furthermore, oligonol attenuated ROS-related inflammation and prevented oxidative damage in our in vitro model of type 2 diabetes. These result indicate oligonol has promising potential as a treatment for T2DM.
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KEYWORD
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Protein tyrosine phosphatase 1B, Diabetes mellitus, Insulin-resistant HepG2 cells, Oligonol, Glucose uptake, Insulin signaling
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