Thioredoxin-interacting protein (TXNIP) expression is induced by glucose, promotes beta cell apoptosis and is essential for glucotoxicity-induced beta cell death, whereas TXNIP deficiency protects against diabetes. Carbohydrate-response element-binding protein (ChREBP/MondoA) is the major transcription factor conferring glucose-induced TXNIP expression. However, we recently discovered that glucose was still able to induce TXNIP in ChREBP knockout mouse islets suggesting the existence of other factors involved in glucose-induced TXNIP regulation. Analyses of the TXNIP 3’UTR revealed several potential miRNA binding sites including miR-93, miR-106b and miR-128. However, using INS-1 beta cells, primary mouse islets and T2D human islets, we found that only miR-128 was downregulated by glucose or diabetes. This suggested that glucose might decrease miR-128 and thereby promote TXNIP expression. In fact, we found overexpression of miR-128 significantly reduced TXNIP mRNA and protein expression whereas inhibition of miR-128 increased beta cell TXNIP expression. Furthermore, luciferase assays using reporter constructs with the wild type TXNIP 3’UTR or a mutated TXNIP 3’UTR confirmed that TXNIP is indeed a direct target of miR-128. Taken together, the results of these studies have identified a novel microRNA directly targeting TXNIP and revealed an alternative, post-transcriptional pathway by which glucose induces TXNIP expression.
G. Jing: None. J. Chen: None. G. Xu: None. A. Shalev: None.