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Recent evidence shows that high glucose levels recruit carbohydrate response element-binding protein,which binds the promoter of thioredoxin-interacting protein (txnip),thereby regulating its expression in 3-cells.Overexpression of txnip not only induces β-cell apoptosis but also reduces insulin production.Thus,the discovery of compounds that either inhibit TXNIP activity or suppress its expression was the focus of the present study.INS-1E cells stably transfected with either a txnip proximal glucose response element connected to a luciferase reporter plasmid (BG73) or full-length txnip promoter connected to a luciferase reporter plasmid (CL108)were used in primary and secondary high-throughput screening campaigns,respectively.From 256 000 synthetic compounds,a small molecule compound,W2476 [9-((1-(4-acetyl-phenyloxy)-ethyl)-2-)adenine],was identified as a modulator of the TXNIP-regulated signaling pathway following the screening and characterized using a battery of bioassays.The preventive and therapeutic properties of W2476 were further examined in streptozotocin-induced diabetic and diet-induced obese mice.Treatment with W2476 (1,5,and 15 μmol/L) dose-dependently inhibited high glucose-induced TXNIP expression at the mRNA and protein levels in INS-1E cells and rat pancreatic islets.Furthermore,W2476 treatment prevented INS-1E cells from apoptosis induced by chronic exposure of high glucose and enhanced insulin production in vitro.Oral administration of W2476 (200 mg·kg-1·d-1) rescued streptozotocin-induced diabetic mice by promoting β-cell survival and enhancing insulin secretion.This therapeutic property of W2476 was further demonstrated by its ability to improve glucose homeostasis and insulin sensitivity in diet-induced obese mice.Thus,chemical intervention of the TXNIPregulated signaling pathway might present a viable approach to manage diabetes.