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

Resveratrol has profound benefits against diabetes. However, whether its methylated derivative 3,4′,5-trimethoxy- trans -stilbene (3,4′,5-TMS) also plays a protective role in glucose metabolism is not characterized. We aimed to study the anti-diabetic effects of 3,4′,5-TMS in vitro and in vivo . Insulin-resistant HepG2 cells (IR-HepG2) were induced by high glucose plus dexamethasone whilst six-week-old male C57BL/6J mice received a 60 kcal% fat diet for 14 weeks to establish an obese diabetic model. 3,4′,5-TMS did not reduce the cell viability of IR-HepG2 cells at concentrations of 0.5 and 1 μM, which enhanced the capability of glycogen synthesis and glucose consumption in IR-HepG2 cells. Four-week oral administration of 3,4′,5-TMS at 10 mg kg −1 day −1 ameliorated insulin sensitivity and glucose tolerance of diet-induced obese (DIO) mice. 3,4′,5-TMS activated the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway by inhibiting phosphorylation of insulin receptor substrate (IRS)-1 at Ser307 and increasing the protein levels of IRS-1 and IRS-2 to restore the insulin signaling pathway in diabetes. 3,4′,5-TMS also upregulated the phosphorylation of glycogen synthase kinase 3 beta (GSK3β) at Ser9. 3,4′,5-TMS suppressed oxidative stress by increasing the protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and NAD(P)H : quinone oxidoreductase 1 (NQO1) and antioxidant enzyme activity. In summary, 3,4′,5-TMS alleviated hepatic insulin resistance in vitro and in vivo , by the activation of the insulin signaling pathway, accomplished by the suppression of oxidative stress. 3,4′,5-Trimethoxy- trans -stilbene (3,4′,5-TMS) alleviates hepatic insulin resistance and oxidative stress through the activation of IRS/PI3K/Akt and Nrf2/NQO1/HO-1 pathways in vitro and in vivo .