DMH1 improves palmitic acid-Induced insulin resistance in cardiomyocytes via PP2A inhibition and AKT/AMPK signaling activation

Our previous studies demonstrated that DMH1 increased glucose metabolism through activating AKT in rat skeletal muscle cells. However, whether DMH1 has a beneficial effect on insulin-resistant cardiomyocytes and the underlying molecular mechanisms remain unclear. In this study, H9c2 cells were treated with 400 µM palmitic acid (PA) for 24 h to induce insulin resistance. Multiple assay kits were used to detect glucose metabolism, cell death, ROS production, and PP2A activity. Western blotting was performed to detect protein expression. Our results showed that DMH1 significantly increased glucose consumption and glucose uptake. DMH1 showed no cytotoxicity in H9c2 cells and activated both AKT and AMPK. PA decreased glucose consumption, glucose uptake, and induced cell death, excessive ROS accumulation, and inactivation of AKT and AMPK. DMH1 attenuated these effects and also improved PA-induced insulin resistance in H9c2 cells. Either an AKT or AMPK inhibitor abolished the beneficial effects of DMH1 on PA-induced insulin-resistant H9c2 cells. Intriguingly, DMH1 inhibited PP2A activity. Moreover, the PP2A activator FTY720-M reversed DMH1-induced AKT and AMPK activation, resulting in complete abolition of the protective role of DMH1 in PA-induced insulin-resistant H9c2 cells. These findings suggest that DMH1 activates AKT and AMPK signaling, thereby ameliorating PA-induced insulin resistance, potentially through inhibition of PP2A activity in H9c2 cells.