Orally Available Small Molecule Regulates TXNIP Expression and Glucagon Action for the Treatment of Diabetes

In the progression of diabetes, sustained glucagon secretion facilitates glucose production. Despite its significance, no treatments currently target this vital parameter. We employed the promoter sequence of thioredoxin-interacting protein (TXNIP) as a screening target, evaluated our in-house chemical library, and subsequently undertook high-throughput screening and optimization via various medicinal chemistry techniques. Our efforts led to the identification of SKL-1223, an orally administered, non-toxic small molecule capable of effectively regulating blood glucose levels in both streptozotocin-induced and obesity-induced (db/db) diabetic mice. Furthermore, our study elucidated the hypoglycemic effect of glucagon and its role in reducing hepatic glucose output. On a mechanistic level, SKL-1223 interacts with the E-box region of the TXNIP promoter, consequently suppressing TXNIP transcription and associated signaling pathways. Thus, our study introduces a novel compound, offering a fresh therapeutic avenue for diabetes beyond existing regimens.