G-Rh4 improves pancreatic β-cells dysfunction in vivo and in vitro by increased expression of Nrf2 and its target genes.

The aim of this study is to investigate the hypoglycemic mechanism of ginsenoside Rh4 (G-Rh4) in vivo and in vitro models. Our results showed that G-Rh4 markedly improved the symptoms of diabetes, normalized glucose metabolism, and promoted insulin secretion which contributed to attenuate symptoms of hyperglycemia in high-fat diet/streptozocin induced type 2 diabetes mellitus mice. This positive effect was associated with increased expression of Nrf2 by G-Rh4. Further results demonstrated that G-Rh4 promoted Nrf2 nucleus translocation as well as up-regulated the expression of HO-1, NQO1 and GCLC. Furthermore, we also found that G-Rh4 increased insulin secretion by activating the signal pathway of PDX-1, GLUT2 and GCK. More importantly, the protective effects of G-Rh4 on alloxan-induced upregulation of Nrf2 target gene and insulin secretion were abolished by Nrf2 knockdown. Finally, we explored the mechanism of G-Rh4 associated with Nrf2 activation and found that the Akt deficiency inhibited G-Rh4-mediated Nrf2 nuclear translocation. Altogether, we present evidence that G-Rh4 increased expression of Nrf2 and results in increased antioxidant gene, as well as a rise in insulin secretion in vivo and in vitro. Exploiting the Nrf2 pathway may show great potential as a therapeutic strategy to improve pancreatic β-cells dysfunction in the diabetic population.