Genipin stimulates glucose transport in C2C12 myotubes via an IRS-1 and calcium-dependent mechanism

Genipin, a compound derived from Gardenia jasminoides Ellis fruits, has been used over the years in traditional Chinese medicine to treat symptoms of type 2 diabetes. However, the molecular basis for its antidiabetic effect has not been fully revealed. In this study, we investigated the effects of genipin on glucose uptake and signaling pathways in C(2)C(12) myotubes. Our study demonstrates that genipin stimulated glucose uptake in a time- and dose-dependent manner. The maximal effect was achieved at 2 h with a concentration of 10 μM. In myotubes, genipin promoted glucose transporter 4 (GLUT4) translocation to the cell surface, which was observed by analyzing their distribution in subcellular membrane fraction, and increased the phosphorylation of Insulin Receptor substrate-1 (IRS-1), Akt, and GSK3β. Meanwhile, genipin increased ATP levels, closed K(ATP) channels, and then increased the concentration of calcium in the cytoplasm in C(2)C(12) myotubes. Genipin-stimulated glucose uptake could be blocked by both the PI3-K inhibitor wortmannin and calcium chelator EGTA. Moreover, genipin increases the level of Reactive Oxygen Species and ATP in C(2)C(12) myotubes. These results suggest that genipin activates IRS-1, PI3-K, and downstream signaling pathway and increases concentrations of calcium, resulting in GLUT4 translocation and glucose uptake increase in C(2)C(12) myotubes.