Novel Small Molecule TXNIP Inhibitor Protects Against Diabetes

Loss of functional beta cell mass represents a major factor in the pathogenesis of diabetes. Currently, there are no therapies that halt this process; however, thioredoxin-interacting protein (TXNIP) has recently emerged as a promising therapeutic target. TXNIP was found to be the top glucose-induced gene in a human pancreatic islet microarray, is increased in diabetes, and TXNIP overexpression results in beta cell apoptosis. TXNIP reduction has shown favorable effects in vivo , where whole body TXNIP-deficient and beta cell-specific TXNIP knockout mice have decreased beta cell apoptosis, increased beta cell mass, elevated insulin levels, and are protected from diabetes. We have also shown that pharmacologic TXNIP inhibition, via the anti-hypertensive medication verapamil, was able to mimic the protective effects of genetic TXNIP deletion and reversed overt diabetes in mice. In addition, it has been established that TXNIP downregulation is beneficial in multiple tissues, making it unnecessary and even undesirable to have a beta cell-specific TXNIP inhibitor and suggesting that detrimental off target effects are unlikely. We have since undertaken a high-throughput screen of 300,000 small molecules that has yielded a novel compound, TI-37330, which is more effective than verapamil in inhibiting TXNIP expression. Moreover, TI-37330 protected primary human islets and INS-1 beta cells against glucose- and cytokine-induced TXNIP and beta cell apoptosis. TI-37330 has also shown in vivo potential as it was found to have good pharmacokinetic properties and was well tolerated in healthy mice. In the context of streptozotocin-induced diabetes, oral administration of TI-37330 promoted beta cell survival, prevented diabetes, and even significantly improved overt diabetes. Collectively, these data establish small molecule TXNIP inhibitors, especially TI-37330, as robust candidates for further development. Disclosure L. Thielen: None. J. Chen: None. G. Xu: None. G. Jing: None. T. Grayson: None. S. Jo: None. A. Shalev: None.