Abstract

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

Resarch Design And Methods: To assess the effects of glucose on TXNIP expression and apoptosis and define the role of TXNIP, we used INS-1 beta cells, primary mouse islets, obese, diabetic BTBR.ob mice and a unique mouse model of TXNIP-deficiency (HcB-19) harboring a natural nonsense mutation in the TXNIP gene.

Results: Incubation of INS-1 cells at 25mM glucose for 24h led to a 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 TUNEL and caspase-3, indicating that TXNIP is a required causal link between glucose-toxicity and beta cell death.

Conclusions: These findings shed new light onto the molecular mechanisms of beta 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 beta cell loss.