Benzyl Isothiocyanate Ameliorates High-Fat Diet-Induced Hyperglycemia by Enhancing Nrf2-Dependent Antioxidant Defense-Mediated IRS-1/AKT/TBC1D1 Signaling and GLUT4 Expression in Skeletal Muscle

Abstract

Obesity caused lipotoxicity, which results in insulin resistance. We studied whether benzyl isothiocyanate (BITC) improved insulin resistance in muscle. BITC was studied <i>in vivo</i> in mice fed a high-fat diet (HFD) and <i>in vitro</i> in C2C12 myotubes treated with palmitic acid (PA). In C2C12 cells, BITC mitigated PA inhibition of glucose uptake and phosphorylation of IRS-1, AKT, and TBC1D1 in response to insulin. BITC upregulated the expression of HO-1, GSTP, and GCLM mRNA and protein as well as GSH contents, which suppressed oxidative damage. Knockdown of Nrf2 abrogated BITC enhancement of antioxidant defense and subsequently reversed BITC protection against PA-induced insulin resistance. Moreover, BITC upregulated the expression of GLUT4, PPARγ, and C/EBPα. In HFD-fed mice, plasma total cholesterol, nonesterified fatty acid, and glucose levels and HOMA-IR were dose-dependently decreased with 0.05 or 0.1% BITC administration. In gastrocnemius muscle, compared with the HFD group, BITC increased the phosphorylation of AKT and TBC1D1, GSH contents, and the expression of antioxidant enzymes as well as GLUT4. These results indicate that BITC ameliorates obesity-induced hyperglycemia by enhancing insulin sensitivity in muscle. This is partly attributed to its inhibition of lipotoxicity-induced oxidative insult and upregulation of GLUT4 expression.