Project Abstracts - CTAR

Start Date: September 30, 2014

End Date:  August 31, 2018

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Abstract

Beta cell death and loss of functional beta cell mass is a major problem of diabetes. Using a human pancreatic islet microarray study to identify glucose-induced genes involved in beta cell death, we discovered thioredoxin-interacting protein (TXNIP) as the top upregulated gene and an attractive target in this regard. TXNIP is a 50kD ubiquitously expressed protein and a member of the thioredoxin system, one of the major cellular redox systems. TXNIP binds to thioredoxin and inhibits its ability to reduce oxidized proteins, thereby leading to a net increase in oxidative stress. More recently, TXNIP has also been found to be involved in inflammasome activation. Diabetes leads to significantly increased TXNIP levels in pancreatic islets and TXNIP in turn promotes beta cell apoptosis. We further found that TXNIP deficient HcB-19 mice harboring a natural non-sense mutation in the TXNIP gene have increased pancreatic beta cell mass, elevated insulin levels and are protected against T1D. Moreover, beta cell-specific knockout of TXNIP in our bTKO mice dramatically reduced beta cell apoptosis, enhanced pancreatic beta cell mass and effectively protected against T1D. We also discovered that pharmacological inhibition of TXNIP expression (by the anti-hypertensive drug and calcium channel blocker verapamil) not only mimics the protective effects of genetic TXNIP deletion, but also reverses overt diabetes. Of note, we and others further found that TXNIP downregulation has beneficial effects in other tissues, especially the heart, making it unnecessary (and even undesirable) for any therapeutic TXNIP inhibition to be beta cell-specific and suggesting that any unwanted off-target effects would be very unlikely. Together, these findings established TXNIP as an attractive therapeutic target for diabetes. However, while we recently discovered a specific novel small molecule TXNIP inhibitor that effectively reduced pro-apoptotic TXNIP in human islets, its effects on in vivo TXNIP expression and beta cell mass especially in the context of T1D remain to be elucidated. Our overarching hypothesis is that TXNIP inhibition using novel specific small molecule TXNIP inhibitors will promote functional beta cell mass in T1D. To test this hypothesis we will analyze the effects and the molecular mechanisms of our TXNIP inhibitors using mouse models of T1D and human islets.

Publications

• Diabetes pathogenic mechanisms and potential new therapies based upon a novel target called TXNIP
• Mir-204 Controls Glucagon-Like Peptide 1 Receptor Expression and Agonist Function
• Islet ChREBP-β is increased in diabetes and controls ChREBP-α and glucose-induced gene expression via a negative feedback loop
• MiR-204 targets PERK and regulates UPR signaling and β-cell apoptosis
• TXNIP regulates myocardial fatty acid oxidation via miR-33a signaling
• Calcium channel blocker use is associated with lower fasting serum glucose among adults with diabetes from the REGARDS study
• Cytokines Regulate β-Cell Thioredoxin-interacting Protein (TXNIP) via Distinct Mechanisms and Pathways
• β-Cell MicroRNAs: Small but Powerful