Resveratrol Upregulates Nrf2 Expression To Attenuate Methylglyoxal-Induced Insulin Resistance in Hep G2 Cells

Abstract

Oxidative stress can result in insulin resistance, a primary cause of type-2 diabetes. Methylglyoxal (MG), a highly reactive dicarbonyl metabolite generated during glucose metabolism, has also been confirmed to cause pancreatic injury and induce inflammation, thereby resulting in insulin resistance. Recently, resveratrol has been reported to exert antioxidant properties, protecting cells from the generation of reactive oxygen species (ROS). The aim of this study was to evaluate resveratrol activation of nuclear factor erythroid 2-related factor 2 (Nrf2) to attenuate MG-induced insulin resistance in Hep G2 cells. Therefore, the molecular signaling events affecting resveratrol-mediated heme oxygenase-1 (HO-1) and glyoxalase expression levels were further investigated in this study. Our findings indicated that resveratrol activated the extracellular signal-regulated kinase (ERK) pathway but not the p38 or c-Jun N-terminal kinase (JNK) pathways, subsequently leading to Nrf2 nuclear translocation and elevation of HO-1 and glyoxalase expression levels. Moreover, resveratrol significantly elevated glucose uptake and protected against MG-induced insulin resistance in Hep G2 cells. In contrast, depletion of Nrf2 by small interfering RNA (si-RNA) resulted in the abrogation of HO-1 and glyoxalase expression in the MG-treated resveratrol group in Hep G2 cells. Administration of an appropriate chemopreventive agent, such as resveratrol, may be an alternative strategy for protecting against MG-induced diabetes.

Mulberry leaves (Morus alba L.) ameliorate obesity-induced hepatic lipogenesis, fibrosis, and oxidative stress in high-fat diet-fed mice

“…In addition, resveratrol has properties to decrease ROS ) and stimulate PPARa involved in fatty acid oxidation (Nakata et al 2012). Moreover, previous studies reported that resveratrol improved insulin resistance by promoting HO-1 protein through mediating Nrf2 level in HepG2 cell (Cheng et al 2012).…”

Natural Nrf2 activators in diabetes

“…Moreover, Nrf2 activation in human liver cells improved glucose uptake [77]. Micro-vascular diabetic complications such as nephropathy [78][79] and neurological dysfunction [80][81] have been evaluated in vitro.…”

Metformin exerts glucose-lowering action in high-fat fed mice via attenuating endotoxemia and enhancing insulin signaling

“…We have previously observed a marked impairment of the Nrf2 system in mice fed a high-fat diet (HFD) [9,10] and that correcting defective Nrf2 function via supplementation with the chemical Nrf2 activator oltipraz not only attenuated oxidative stress but also improved insulin signaling and glucose metabolism [10] . Other synthetic chemical Nrf2 activators and natural Nrf2-activating compounds have also been shown to be effective in improving insulin action and glucose metabolism in various insulin-resistant models [9,[11][12][13] . In addition, there is probably an interaction between oxidative stress and inflammatory activation.…”