Pancreatic beta-cell apoptosis is a key feature of diabetes and finding a target to block this process and thereby preserve the patient’s own beta-cell mass and insulin production would represent a major breakthrough for diabetes therapy. Dr. Shalev’s laboratory identified thioredoxin-interacting protein (TXNIP) (a protein involved in the cellular redox state) as such a potential target. When performing the first human islet microarray study, Shalev found that TXNIP was the most dramatically up-regulated gene in response to glucose, suggesting that it might play an important role in beta-cell biology. Subsequent analysis of the TXNIP promoter revealed that a unique carbohydrate response element was responsible for this glucose-induced TXNIP transcription. The Shalev group went on to show that TXNIP expression is increased in islets of mice with diabetes and that TXNIP overexpression induces beta-cell apoptosis. Moreover, TXNIP plays a critical role in linking glucose toxicity to beta-cell death and TXNIP deficiency promotes beta-cell survival. In fact, generalized or just beta-cell-specific reduction of TXNIP expression was able to rescue mice from type 1 and type 2 diabetes proving that TXNIP represents an attractive therapeutic target. However, still very little is known about the processes controlling TXNIP and the Shalev lab is therefore now employing molecular biological in vitro approaches, as well as cell culture and various in vivo mouse models, to study the molecular mechanisms and signaling pathways involved in TXNIP regulation and function. Additional projects focus on the role of TXNIP in diabetic complications including diabetic cardiomyopathy and heart failure.