Molecular biology of diabetes, beta cell biology, apoptosis, oxidative stress, transcriptional regulation of gene expression, diabetes complications
Research Description: Diabetes is a rapidly growing public health issue characterized by elevated blood glucose levels and high morbidity and mortality. Under normal conditions, insulin, a hormone produced exclusively in the pancreatic beta cells, maintains blood glucose levels within the normal range. Loss of these pancreatic beta cells by programmed cell death (apoptosis) is a key feature of diabetes. Therefore, finding a target that could be used to block beta cell apoptosis and thereby preserve the patient’s own beta cell mass and insulin production would represent a major breakthrough for diabetes therapy. However, the mechanisms involved in beta cell death are not well understood. 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 pancreatic 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 the islets of mice with diabetes and that TXNIP overexpression induces beta cell apoptosis. Moreover, the Shalev lab found that TXNIP plays a critical role in linking glucose toxicity to beta cell death and that 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 ongoing projects focus on the role of TXNIP in diabetic complications including diabetic cardiomyopathy and heart failure.