Thioredoxin-Interacting Protein

A Critical Link Between Glucose Toxicity and β-Cell Apoptosis

  1. Anath Shalev1
  1. 1Department of Medicine, University of Wisconsin, Madison, Wisconsin
  2. 2Department of Medicine, University of California, Los Angeles, California
  1. Address correspondence and reprint requests to Anath Shalev, MD, University of Wisconsin-Madison, H4/526 Clinical Science Center, 600 Highland Ave., Madison, WI 53792. E-mail: as7{at}medicine.wisc.edu

Abstract

OBJECTIVE—In diabetes, glucose toxicity affects different organ systems, including pancreatic islets where it leads to β-cell apoptosis, but the mechanisms are not fully understood. Recently, we identified thioredoxin-interacting protein (TXNIP) as a proapoptotic β-cell factor that is induced by glucose, raising the possibility that TXNIP may play a role in β-cell glucose toxicity.

RESEARCH DESIGN AND METHODS—To assess the effects of glucose on TXNIP expression and apoptosis and define the role of TXNIP, we used INS-1 β-cells; primary mouse islets; obese, diabetic BTBR.ob mice; and a unique mouse model of TXNIP deficiency (HcB-19) that harbors a natural nonsense mutation in the TXNIP gene.

RESULTS—Incubation of INS-1 cells at 25 mmol/l glucose for 24 h led to an 18-fold increase in TXNIP protein, as assessed by immunoblotting. This was accompanied by increased apoptosis, as demonstrated by a 12-fold induction of cleaved caspase-3. Overexpression of TXNIP revealed that TXNIP induces the intrinsic mitochondrial pathway of apoptosis. Islets of diabetic BTBR.ob mice also demonstrated increased TXNIP and apoptosis as did isolated wild-type islets incubated at high glucose. In contrast, TXNIP-deficient HcB-19 islets were protected against glucose-induced apoptosis as measured by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and caspase-3, indicating that TXNIP is a required causal link between glucose toxicity and β-cell death.

CONCLUSIONS—These findings shed new light onto the molecular mechanisms of β-cell glucose toxicity and apoptosis, demonstrate that TXNIP induction plays a critical role in this vicious cycle, and suggest that inhibition of TXNIP may represent a novel approach to reduce glucotoxic β-cell loss.

  • Received May 25, 2007.
  • Accepted December 23, 2007.
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This Article

  1. Diabetes vol. 57 no. 4 938-944
  1. All Versions of this Article:
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