Title: Identification of an Anti-diabetic, Orally Available Small Molecule that Regulates TXNIP Expression and Glucagon Action
Author: Lance A. Thielen, Junqin Chen, Gu Jing, Omar Moukha-Chafiq, Guanlan Xu, SeongHo Jo, Truman B. Grayson, Brian Lu, Peng Li, Corinne E. Augelli-Szafran, Mark J. Suto, Matt Kanke, Praveen Sethupathy, Jason K. Kim, Anath Shalev
Abstract: Diabetes is characterized by hyperglycemia, loss of functional islet beta cell mass,deficiency of glucose-lowering insulin, and persistent alpha cell secretion of gluconeogenicglucagon. Still, no therapies that target these underlying processes are available.We therefore performed high-throughput screening of 300,000 compounds and extensivemedicinal chemistry optimization and here report the discovery of SRI-37330, an orallybioavailable, non-toxic small molecule, which effectively rescued mice from streptozotocin-and obesity-induced (db/db) diabetes. Interestingly, in rat cells and in mouse and human islets, SRI-37330 inhibitedexpression and signaling of thioredoxin-interacting protein, which we have previouslyfound to be elevated in diabetes and to have detrimental effects on islet function.In addition, SRI-37330 treatment inhibited glucagon secretion and function, reducedhepatic glucose production, and reversed hepatic steatosis. Thus, these studies describea newly designed chemical compound that, compared to currently available therapies,may provide a distinct and effective approach to treating diabetes.