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

Academic Article

Abstract

  • 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 β-cells and the mechanism of its regulation by glucose remain unknown. We therefore generated a stable transfected β-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 β-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 β-cell gene elevated in insulin resistance/diabetes and up-regulated by glucose through a unique ChoRE and may link glucotoxicity and β-cell apoptosis. Copyright © 2005 by The Endocrine Society.
  • Authors

    Published In

  • Endocrinology  Journal
  • Digital Object Identifier (doi)

    Author List

  • Minn AH; Hafele C; Shalev A
  • Start Page

  • 2397
  • End Page

  • 2405
  • Volume

  • 146
  • Issue

  • 5