alexa Involvement of thioredoxin-interacting protein (TXNIP) in glucocorticoid-mediated beta cell death.


Journal of Clinical & Experimental Ophthalmology

Author(s): Reich E, Tamary A, Sionov RV, Melloul D

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Abstract AIM/HYPOTHESIS: Glucocorticoid hormones (GCs) are widely used to treat a variety of inflammatory and immune diseases. However, their long-term administration is associated with adverse metabolic effects, including glucose intolerance and diabetes. Our objective was to elucidate the mechanisms by which GCs affect beta cell survival with a specific emphasis on the role of the thioredoxin-interacting protein (TXNIP) in beta cell apoptosis. METHODS: Human and mouse islets, together with MIN6 beta cells, were exposed to dexamethasone (Dex) and apoptosis was assessed by measuring the percentage of sub-G1 cells, the appearance of cleaved caspase-3 or by using a TUNEL assay. Dex-upregulated expression of Txnip mRNA was analysed by real-time PCR, and GC-modulated production and modification of proteins were determined by western blotting. RESULTS: We provide evidence that TXNIP, a negative regulator of the antioxidant thioredoxin (TRX), is strongly induced in beta cells by GCs and that its induction is dependent on p38 mitogen-activated protein kinase (MAPK) activation. TXNIP downregulation by RNA interference, overexpression of the radical scavenger TRX1 or elevation of intracellular cAMP levels attenuated the Dex-mediated apoptosis. Dex-induced Txnip expression and beta cell apoptosis are mediated by the glucocorticoid receptor (GR), as the GR antagonist RU486 fully abolishes these effects. CONCLUSIONS/INTERPRETATION: Altogether, our data suggest TXNIP as a novel mediator of GC-induced apoptosis in beta cells and further contribute to our understanding of beta cell death pathways. This article was published in Diabetologia and referenced in Journal of Clinical & Experimental Ophthalmology

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