Imeglimin Alleviates High-Glucose-Induced Bioenergetic and Oxidative Stress Thereby Enhancing Intercellular Adhesion in H9c2 Cardiomyoblasts

To elucidate the effects of the new antidiabetic agent, imeglimin (Ime, 2 mM), on high-glucose-induced cellular stress in cardiac cells, its effects were compared with those of the conventional antidiabetic agent metformin (Met, 2 mM) based on various cellular pathophysiological functions. H9c2 cardiomyoblasts were cultured under normal-glucose (5.5 mM, N-Glu) or high-glucose (50 mM, H-Glu) conditions. Cellular metabolic function was evaluated using a Seahorse XFe96 Bioanalyzer, along with measurements of reactive oxygen species (ROS) production, expression levels of the autophagy-related marker LC3, and intercellular adhesion properties measured based on transepithelial electrical resistance (TEER). Cells cultured under H-Glu conditions showed enhanced mitochondrial and glycolytic activities, which were suppressed by Met or Ime. Under H-Glu conditions, total cellular ROS (t-ROS) levels were significantly increased. Met had little effect on t-ROS under H-Glu conditions, whereas Ime markedly reduced both t-ROS and mitochondrial ROS (m-ROS) levels under H-Glu conditions. The LC3-II/LC3-I ratio, a marker of autophagic activity, decreased under H-Glu conditions; however, this reduction was not significantly affected by treatment with either Met or Ime. Regarding intercellular adhesion properties, TEER values were elevated under H-Glu conditions compared to N-Glu conditions, and those under H-Glu conditions were further increased by Ime but not Met. In support of these results, the mRNA levels of cell-adhesion-related molecules, including β-catenin and N-cadherin, were also altered by Ime. Collectively, Ime modulated high-glucose-induced alterations in the biological properties of H9c2 cardiomyoblasts, independent of changes in autophagic activity.