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Thioredoxin-Interacting Protein Is Stimulated by Glucose through a Carbohydrate Response Element and Induces ß-Cell Apoptosis

Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53792

Address all correspondence to: Anath Shalev, M.D., University of Wisconsin-Madison, H4/526 Clinical Science Center, 600 Highland Avenue, Madison, Wisconsin 53792. E-mail: as7{at}medicine.wisc.edu.

Recently, we identified thioredoxin-interacting protein (TXNIP) as the most dramatically glucose-induced gene in our human islet microarray study. TXNIP is a regulator of the cellular redox state, but its role in pancreatic ß-cells and the mechanism of its regulation by glucose remain unknown. We therefore generated a stable transfected ß-cell line (INS-1) overexpressing human TXNIP and found that TXNIP overexpression induced apoptosis as assessed by Bax, Bcl2, caspase-3, and cleaved caspase-9 as well as Hoechst staining. Interestingly, islets of insulin-resistant/diabetic mice (AZIP-F1, BTBRob/ob) demonstrated elevated TXNIP expression, suggesting that TXNIP may play a role in glucotoxicity and the ß-cell loss observed under these conditions. Furthermore, we found that glucose-induced TXNIP transcription is not dependent on glucose metabolism and is mediated by a distinct carbohydrate response element (ChoRE) in the human TXNIP promoter consisting of a perfect nonpalindromic repeat of two E-boxes. Transfection studies demonstrated that this ChoRE was necessary and sufficient to confer glucose responsiveness. Thus, TXNIP is a novel proapoptotic ß-cell gene elevated in insulin resistance/diabetes and up-regulated by glucose through a unique ChoRE and may link glucotoxicity and ß-cell apoptosis.

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