DA-9701 (Motilitone®) improves glucose homeostasis by protecting STZ-induced β-cells death

Beta-cell death is a common characteristic driving the loss of insulin secretion and hyperglycemia in patients with diabetes mellitus (DM). Considering the characteristics of DM, strategies that preserve β-cell mass by preventing apoptosis may be effective in improving glucose homeostasis. Here, we investigated the novel mechanism of DA-9701 (Motilitone®), an approved botanical drug for functional dyspepsia, as a therapeutic option for controlling blood glucose levels by preserving β-cell mass. DA-9701 was administered to both streptozotocin (STZ)-induced diabetic and ob/ob mice, representing insulin-deficient and insulin-resistant models, respectively. In STZ-induced mice, DA-9701 improved glucose homeostasis, increased β-cell mass, and reduced cleaved caspase-3 expression in the pancreatic tissue. Similar anti-apoptotic effects were observed in MIN6 cells treated with STZ, where DA-9701 restored cell viability and decreased cleaved caspase-3 levels. In ob/ob mice, DA-9701 increased β-cell mass and insulin levels; however, it failed to improve glucose tolerance, suggesting no significant effect on insulin sensitivity. DA-9701 did not alter β-cell mass or viability under normal conditions in vivo and in vitro, indicating that its protective effect is specific to pathological states. These findings suggest that DA-9701 improves glucose homeostasis primarily by reducing β-cell apoptosis rather than enhancing proliferation in the STZ model. Given that DA-9701 is already approved for clinical use and has a known safety profile, it is a promising candidate for repurposing as a β-cell-preserving agent in diabetes therapy.