C2C12 Muscle Myotubes, but not Kidney Proximal Tubule HK-2 Cells, Elevate Erythritol Synthesis in Response to Oxidative Stress

BACKGROUND: As a biomarker, elevated serum erythritol concentrations predict type 2 diabetes and cardiovascular disease onset. Erythritol was recently shown to be a product of human glucose metabolism through the pentose phosphate pathway. The regulation of erythritol synthesis from glucose has been explored in cancer cells but not in nontransformed cells. OBJECTIVE: The kidneys and skeletal muscle have increased erythritol content in response to dietary sucrose, which suggests that they may significantly contribute to circulating erythritol concentrations. In the present study, we evaluated if conditions that promote erythritol synthesis in cancer cells are consistent in skeletal muscle and kidney cells. METHODS: C2C12 myotubules were used as a model for skeletal muscle, and human kidney (HK)-2 human proximal tubule cells were used to model kidney. C2C12 cells were exposed to high- or low-glucose conditions. Both C2C12 and HK-2 cells were exposed to the free radical generator menadione, then intracellular reactive oxygen species (ROS) and erythritol concentrations were measured. Intracellular sorbitol concentrations were also measured because increased polyol flux was also observed after exposure to excess glucose and oxidative stress. RESULTS: Intracellular erythritol concentrations were significantly elevated in C2C12 cells following both high-glucose and menadione treatment. In contrast, HK-2 cells did not increase erythritol synthesis in response to oxidative stress. Generation of ROS through hydrogen peroxide exposure elevated sorbitol concentrations in both C2C12 and HK-2 cells, whereas generation of radicals with menadione treatment did not affect sorbitol production in either cell type. CONCLUSIONS: These findings highlight that the factors contributing to elevated erythritol synthesis vary between cell types. More specifically, these studies demonstrate that muscle cells increase erythritol synthesis in response to both high glucose in culture medium and oxidative stress, whereas kidney cells increase erythritol synthesis only in response to high glucose.