3,3′,4,5′-Tetramethoxy-trans-stilbene Improves Insulin Resistance by Activating the IRS/PI3K/Akt Pathway and Inhibiting Oxidative Stress

Abstract

The potential anti-diabetic effect of resveratrol derivative, 3,3′,4,5′-tetramethoxy-trans-stilbene (3,3′,4,5′-TMS) and its underlying mechanism in high glucose (HG) and dexamethasone (DXMS)-stimulated insulin-resistant HepG2 cells (IR-HepG2) were investigated. 3,3′,4,5′-TMS did not reduce the cell viability of IR-HepG2 cells at the concentrations of 0.5–10 µM. 3,3′,4,5′-TMS increased the potential of glucose consumption and glycogen synthesis in a concentration-dependent manner in IR-HepG2 cells. 3,3′,4,5′-TMS ameliorated insulin resistance by enhancing the phosphorylation of glycogen synthase kinase 3 beta (GSK3β), inhibiting phosphorylation of insulin receptor substrate-1 (IRS-1), and activating phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway in IR-HepG2 cells. Furthermore, 3,3′,4,5′-TMS significantly suppressed levels of reactive oxygen species (ROS) with up-regulation of nuclear factor erythroid 2-related factor 2 (Nrf2) expression. To conclude, the beneficial effect of 3,3′,4,5′-TMS against insulin resistance to increase glucose consumption and glycogen synthesis was mediated through activation of IRS/PI3K/Akt signaling pathways in the IR-HepG2 cells, accomplished with anti-oxidative activity through up-regulation of Nrf2.

Selenoprotein F Knockout Caused Glucose Metabolism Disorder in Young Mice by Disrupting Redox Homeostasis

“…AKT activation can further induce glycogen synthesis through increasing phosphorylation of GSK3β and inhibit gluconeogenesis through increasing phosphorylation of FoxO1 [ 47 ]. A certain degree of oxidative stress can reduce insulin sensitivity by suppressing the AKT signaling pathway leading to insulin resistance [ 45 , 48 ]. Once the phosphorylation of AKT is inhibited, the phosphorylation levels of GSK3β and FoxO1 also decrease, which causes decreased glycogen synthesis and increased gluconeogenesis [ 48 , 49 ].…”

“…A certain degree of oxidative stress can reduce insulin sensitivity by suppressing the AKT signaling pathway leading to insulin resistance [ 45 , 48 ]. Once the phosphorylation of AKT is inhibited, the phosphorylation levels of GSK3β and FoxO1 also decrease, which causes decreased glycogen synthesis and increased gluconeogenesis [ 48 , 49 ]. Therefore, decreased insulin sensitivity in mice is often accompanied by reduced expression levels of phosphorylated AKT, FoxO1 and GSK3β (normalized to unphosphorylated AKT, FoxO1 and GSK3β, respectively) [ 49 , 50 ].…”

3,4′,5-Trimethoxy-trans-stilbene ameliorates hepatic insulin resistance and oxidative stress in diabetic obese mice through insulin and Nrf2 signaling pathways

“…An insulin resistant cell model was triggered by a combination of DXMS and high glucose as previously reported. 32,33 DXMS exacerbates the onset of insulin resistance and oxidative stress in a hyperglycemic environment by interfering with insulin signaling and impairing mitochondrial function. 34 HepG2 cells were pretreated with DXMS (30 μM, dissolved in ethanol) and d -glucose (50 mM final concentration) for 48 h. Thereafter, the experimental groups were treated with different concentrations of 3,4′,5-TMS (0.5 and 1 μM) for 16 h. The group not treated with DXMS, d -glucose and 3,4′,5-TMS served as the control.…”

The protective role of resveratrol in diabetic wound healing

“…Javed et al (2022) depicted that resveratrol (30 mg/kg, intraperitoneal injection) could reduce IR and restore its normal histopathology in enteroendocrine L cells by facilitating the expression of glucagon‐like peptide‐1(GLP‐1). Also, Tan et al (2022) showed that resveratrol derivative (3,3′,4,5′‐tetramethoxy‐trans‐stilbene, 3,3′,4,5′‐TMS) (0.5–10 μM) could fight against IR in HepG2 cells of which the underlying mechanism was activating insulin receptor substrate‐1 (IRS)/PI3K/Akt signaling pathway and upregulating NF‐E2‐related factor (Nrf2). Second, glycometabolism disorder is the principal characteristic of DM, and it is of great significance for treating DM to correct the glycemetabolism disorder (Li et al, 2022).…”