September 2013 Research Spotlight : Anath Shalev

shalev-Lab
Dr. Anath Shalev is a Professor of Medicine in the Division of Endocrinology, Diabetes, and Metabolism at the University of Alabama at Birmingham (UAB). She is the Director of the UAB Comprehensive Diabetes Center and the Nancy R. and Eugene C. Gwaltney Family Endowed Chair in Juvenile Diabetes Research.


Dr. Shalev received her Medical Degree and training at the University of Basel, Switzerland and took a postgraduate course at the University of Zurich, Switzerland. She then came to the U.S. as a research fellow at Harvard Medical School, Boston, MA, and did her fellowship training in Endocrinology, Diabetes and Metabolism at the National Institutes of Health in Bethesda, MD. She became an Assistant Professor at the University of Wisconsin-Madison and was later promoted to Associate Professor and Director of Endocrinology, Diabetes and Metabolism Research there.
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Dr. Shalev moved to UAB in 2010 to become the Director of the UAB Comprehensive Diabetes Center and a Professor of Medicine. Dr. Shalev was awarded a Swiss National Science Foundation Scholarship and ESPEN Ajinomoto Fellowship Award. She also was awarded a Scientific Achievement Award at the Rachmiel Levine Diabetes and Obesity Symposium.


Dr. Shalev’s laboratory identified thioredoxin-interacting protein (TXNIP) (a protein involved in the cellular redox state) to be increased in pancreatic islets of mice with diabetes and demonstrated 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, genetic deletion or pharmacological inhibition (with calcium channel blockers) of TXNIP expression was able to rescue mice from type 1 and type 2 diabetes proving that TXNIP represents an attractive therapeutic target. Most recently the Shalev Lab discovered that TXNIP also controls beta cell function and inhibits insulin production by regulating a specific microRNA that in turn modulates a prominent insulin transcription factor. However, the processes controlling TXNIP are still not fully understood 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 drug discovery and the role of TXNIP in diabetic complications including diabetic cardiomyopathy and heart failure.

Dr. Shalev is a member of the Endocrine Society, American Diabetes Association, American Heart Association, and American Society of Clinical Investigation. Dr. Shalev also serves as a reviewer for prestigious journals, including Nature, Science, and Diabetes and is a permanent NIH study section member.

Abstract
Beta-cell dysfunction and impaired insulin production are hallmarks of diabetes, but despite the growing diabetes epidemic, the molecular mechanisms underlying this disease have remained unclear. We identified thioredoxin-interacting protein (TXNIP), a cellular redox regulator, as a crucial factor in beta-cell biology and show that beta-cell TXNIP is upregulated in diabetes, whereas TXNIP deficiency protects against diabetes by preventing beta-cell apoptosis. Here we show that TXNIP and diabetes induce beta-cell expression of a specific microRNA, miR-204, which in turn blocks insulin production by directly targeting and downregulating MAFA, a known insulin transcription factor. In particular, we first discovered the regulation of miR-204 by TXNIP by microarray analysis, followed by validation studies in INS-1 beta cells, islets of Txnip-deficient mice, diabetic mouse models and primary human islets. We then further found that TXNIP induces miR-204 by inhibiting the activity of signal transducer and activator of transcription 3 (STAT3), a transcription factor that is involved in miR-204 regulation. We also identified MAFA as a target that is downregulated by miR-204. Taken together, our results demonstrate that TXNIP controls microRNA expression and insulin production and that miR-204 is involved in beta-cell function. The newly identified TXNIP-miR-204-MAFA-insulin pathway may contribute to diabetes progression and provides new insight into TXNIP function and microRNA biology in health and disease.

Research Interests
Loss of pancreatic beta cells by apoptosis is a key feature of type 1 and type 2 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, genetic deletion or pharmacological inhibition (with calcium channel blockers) of TXNIP expression was able to rescue mice from type 1 and type 2 diabetes proving that TXNIP represents an attractive therapeutic target. Most recently the Shalev Lab discovered that TXNIP also controls beta cell function and inhibits insulin production by regulating a specific microRNA that in turn modulates a prominent insulin transcription factor. However, the processes controlling TXNIP are still not fully understood 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