Activation of Estrogen Receptor Is Crucial for Resveratrol-Stimulating Muscular Glucose Uptake via Both Insulin-Dependent and -Independent Pathways

Abstract

OBJECTIVE-Estradiol (E 2 ) is known to modulate insulin sensitivity and, consequently, glucose homeostasis. Resveratrol (RSV), an agonist of estrogen receptor (ER), has exerted antihyperglycemic effects in streptozotocin-induced type 1 diabetic rats in our previous study and was also shown to improve insulin resistance in other reports. However, it remains unknown whether activation of ER is involved in the metabolic effects of RSV via insulin-dependent and -independent mechanisms. RESEARCH DESIGN AND METHODS-MaleSprague-Dawley rats were given a high cholesterol-fructose (HCF) diet for 15 weeks and were treated with RSV for either 15 days or 15 weeks.RESULTS-Here, we show that RSV shifts the metabolic characteristics of rats on an HCF diet toward those of rats on a standard diet. RSV treatment increased insulin-stimulated wholebody glucose uptake and steady-state glucose uptake of soleus muscle and liver in HCF-fed rats as well as enhanced membrane trafficking activity of GLUT4 and increased phosphorylation of insulin receptor in insulin-resistant soleus muscles. Interestingly, the phosphorylated ER level in insulin-resistant soleus muscle was significantly elevated in rats with RSV treatment in both basal and euglycemic-hyperinsulinemic conditions. RSV exerted an insulin-like stimulatory effect on isolated soleus muscle, epididymal fat and hepatic tissue, and C2C12 myotubes. The RSV-stimulated glucose uptake in C2C12 myotubes was dependent on extracellular signal-related kinase/p38 (early phase, 1 h) and p38/phosphoinositide 3-kinase (late phase, 14 h) activation. Inhibition of ER abrogated RSV-induced glucose uptake in both early and late phases.CONCLUSIONS-Collectively, these results indicate that ER is a key regulator in RSV-stimulating insulin-dependent and -independent glucose uptake, which might account for the protective effects of RSV on diet-induced insulin resistance syndrome.

Hydro-Alcoholic Cinnamon Extract, Enhances Glucose Transporter Isotype-4 Translocation from Intracellular Compartments into the Cytoplasmic Membrane of C2C12 Myotubes

“…The later result is in accordance with our study result; in our study also HACE had increased GLUT4 contents of muscular tissue culture model, C2C12 myotubes that this effect was dosedependent (see results). Also Deng et al [34] have shown that resveratrol, an ingredient of Polygonum cuspidatum and red wine did enhance glucose uptake and GLUT4 movement to the CM in C2C12 myotubes. However, other in vivo, ex vivo studies and human trials which have been explored antidiabetic effect or mechanism by which cinnamon exert antidiabetic effect all are in accordance with our study results [14,16,[35][36][37][38].…”

Resveratrol reduces chronic inflammation and improves insulin action in the myocardium of high-fat diet-induced obeserats

“…However, changes in inflammation levels and myocardial insulin signaling pathway require further investigation. Additionally, nutrients like resveratrol improve insulin sensitivity 19,23 and reduce inflammation and incidence of coronary diseases 16 . Thus, the study hypothesis was that resveratrol supplementation could benefit the myocardial insulin signaling pathway of obese rats.…”

“…The resveratrol has also been shown to benefit the insulin signaling pathway 21,23 . Resveratrol supplementation increased IRS1 and Akt phosphorylation in the liver and soleus muscle of insulin-resistant rats, and reduced blood glucose and insulin 21 .…”

Resveratrol: A miraculous natural compound for diseases treatment

“…Data confirmed the effect of RSV on oxidative stress reduction in skeletal muscle (Chang et al., 2014). It is noteworthy that RSV affects skeletal muscles by increasing GLUT4 expression and augmenting intracellular glucose transport (Deng, Hsieh, Huang, Lu, & Hung, 2008). RSV was also found to reduce gluconeogenesis activity and increase liver glycogenesis, which leads to hepatic glucose output reduction.…”

“…Actually, activation of these targets by RSV as a drug led to cellular and enzymatic phenomena including decreased lipid accumulation, inflammation, and oxidative damage in liver, muscle, and adipocyte tissues and finally led to insulin action improvement in type 2 diabetes (Figure 5). However, another possible mechanism suggested in different studies including increased phosphorylation of insulin receptor, IRS‐1 expression, and phosphorylation of Akt (Chen, Li et al., 2012; Deng et al., 2008). In another in vivo study conducted by Cheng et al., it has been shown that resveratrol promoted nuclear factor erythroid 2‐related factor‐2 (Nrf2) phosphorylation, in the pancreas of methylglyoxal‐treated mice.…”