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

Alexandra H Minn1, Christian Hafele, Anath Shalev

  • 1Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53792, USA. ahm@medicine.wisc.edu

Endocrinology
|February 12, 2005
PubMed

Insights

Thioredoxin-interacting protein (TXNIP) is a novel proapoptotic gene in pancreatic beta-cells. Elevated TXNIP in diabetes links high glucose to beta-cell death via a unique carbohydrate response element.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Cell Biology

Background:

  • Thioredoxin-interacting protein (TXNIP) is a glucose-induced gene in human islets.
  • The role of TXNIP in pancreatic beta-cells and its glucose regulation mechanism are unknown.

Purpose of the Study:

  • Investigate TXNIP's function in beta-cells.
  • Elucidate the mechanism of glucose-induced TXNIP regulation.
  • Determine TXNIP's role in insulin resistance and diabetes.

Main Methods:

  • Generated a stable beta-cell line overexpressing human TXNIP.
  • Assessed apoptosis using Bax, Bcl2, caspase-3, cleaved caspase-9, and Hoechst staining.
  • Analyzed TXNIP expression in islets from diabetic mouse models.
  • Performed transfection studies to identify the glucose-responsive element in the TXNIP promoter.

Main Results:

  • TXNIP overexpression induced beta-cell apoptosis.
  • Elevated TXNIP expression was observed in islets of insulin-resistant/diabetic mice.
  • Glucose-induced TXNIP transcription is independent of glucose metabolism.
  • A novel carbohydrate response element (ChoRE) containing two E-boxes mediates glucose responsiveness.

Conclusions:

  • TXNIP is a novel proapoptotic gene in beta-cells.
  • Elevated TXNIP in diabetes may contribute to glucotoxicity and beta-cell loss.
  • Glucose up-regulates TXNIP via a unique ChoRE, linking glucotoxicity to beta-cell apoptosis.

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