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.
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.
Authors: F Delaunay; A Khan; A Cintra; B Davani; Z C Ling; A Andersson; C G Ostenson; J Gustafsson; S Efendic; S Okret Journal: J Clin Invest Date: 1997-10-15 Impact factor: 14.808
Authors: Junqin Chen; Simon T Hui; Francesca M Couto; Imran N Mungrue; Dawn B Davis; Alan D Attie; Aldons J Lusis; Roger A Davis; Anath Shalev Journal: FASEB J Date: 2008-06-13 Impact factor: 5.191
Authors: Anath Shalev; Cynthia A Pise-Masison; Michael Radonovich; Steven C Hoffmann; Boaz Hirshberg; John N Brady; David M Harlan Journal: Endocrinology Date: 2002-09 Impact factor: 4.736