Development of Hydrogen Sulfide-Donating Silybin Derivatives with a Type-2 Diabetes Mellitus-Alleviating Effect through Improving Intestinal L-Cell Functions.

GLP-1 is an incretin hormone that maintains glucose homeostasis. Given the reduced plasma H2S levels observed in patients with type-2 diabetes mellitus (T2DM) and the stimulatory effect of H2S donors on GLP-1 secretion small-molecule gasotransmitter drugs based on H2S donors have emerged as an alternative strategy for treating T2DM via increasing GLP-1 levels. In this context, H2S donating silybin derivative bin-4 was discovered. By the upregulation of the PI3K/AKT/GSK-3β pathway, bin-4 facilitated Nrf2 nuclear translocation to inhibit oxidative damage and apoptosis in GLUTag cells. Additionally, activation of estrogen receptor α enabled bin-4 to enhance GLP-1 secretion by 30%. In vivo, bin-4 effectively decreased blood glucose levels by 63.1%, enhanced insulin secretion by 90.2%, and boosted GLP-1 production by 91.2%. It also exhibited acceptable toxicity profiles in T2DM mice, with potential metabolites identified and proposed. Overall, bin-4 demonstrated a potent T2DM-alleviating effect, providing the theoretical foundation for the design of candidate gasotransmitter-based drugs.