A Critical Link Between Glucose Toxicity and β-Cell Apoptosis
- 1Department of Medicine, University of Wisconsin, Madison, Wisconsin
- 2Department of Medicine, University of California, Los Angeles, California
- 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:
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.
- ER, endoplasmic reticulum
- INS-LacZ, INS-1 cells overexpressing LacZ
- INS-TXNIP, INS-1 cells with constitutive TXNIP overexpression
- HBSS, Hanks' balanced salt solution
- TUNEL, transferase-mediated dUTP nick-end labeling
- TXNIP, thioredoxin-interacting protein
- Received May 25, 2007.
- Accepted December 23, 2007.