Dual antidiabetic potential of arjunglucoside I and arjunetin from Terminalia chebula via modulation of insulin- and gluconeogenesis-related responses

A deciduous tree belonging to the Combretaceae family, Terminalia chebula Retz. has a long history of traditional use in diabetes management. However, it is not fully understood how the extract of T. chebula exerts the antidiabetic effects. To identify the constituents responsible for this activity, we investigated the bark of T. chebula and determined the structures of compounds exhibiting antidiabetic potential. Using molecular networking, LC-MS, and NMR analysis, we identified five phytochemical compounds (1–5): arjunglucoside I (1), arjunetin (2), arjungenin (3), (–)-catechin (4), and (–)-epicatechin (5). We found that arjunglucoside I and arjunetin selectively inhibited α-glucosidase, but not α-amylase, suggesting that they may regulate postprandial glucose levels with few gastrointestinal side effects. Both compounds significantly increased the gene expression of insulin (ins) but decreased that of pck1, which encodes phosphoenolpyruvate carboxykinase (PEPCK), a key enzyme in gluconeogenesis. These effects were also observed under metabolic stress induced by cAMP/dexamethasone, indicating feedback regulation between insulin and gluconeogenesis pathways. Arjunglucoside I and arjunetin protected zebrafish from oxidative damage induced by alloxan, modulated calcium signaling-related gene expression under insulin-resistant conditions, and increased glucose uptake in insulin-resistant C2C12 myotubes. Collectively, these results provide insights into the use of arjunglucoside I and arjunetin for diabetes treatment and the development of novel antidiabetic agents derived from the promising phytochemicals.