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This version published online on February 10, 2005
Endocrinology, doi:10.1210/en.2004-1378
A more recent version of this article appeared on May 1, 2005
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Submitted on October 20, 2004
Accepted on January 31, 2005

Thioredoxin-interacting protein is stimulated by glucose through a carbohydrate response element and induces {beta} cell apoptosis

Alexandra H. Minn, Christian Hafele, and Anath Shalev*

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

* To whom correspondence should be addressed. 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 {beta} cells and the mechanism of its regulation by glucose remain unknown.

We therefore generated a stable transfected {beta} cell line (INS-1) overexpressing human TXNIP and found that TXNIP-overexpression induced apoptosis as assessed by Bax, Bcl2, and caspase-3, 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 {beta} 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 non-palindromic repeat of two E-boxes. Transfection studies demonstrated that this ChoRE was necessary and sufficient to confer glucose responsiveness.

Thus, TXNIP is a novel pro-apoptotic {beta} cell gene elevated in insulin resistance/diabetes and upregulated by glucose through a unique ChoRE and may link glucotoxicity and {beta} cell apoptosis.
Key words: diabetes • pancreatic islets • glucotoxicity




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