%0 Journal Article %T W2476 ameliorates β-cell dysfunction and exerts therapeutic effects in mouse models of diabetes via modulation of the thioredoxin-interacting protein signaling pathway %A LI Ting %A LIN Guang-yao %A ZHONG Li %A ZHOU Yan %A WANG Jia %A ZHU Yue %A FENG Yang %A CAI Xiao-qing %A LIU Qing %A NOSJEAN Olivier %A BOUTIN Jean A %A RENARD Pierre %A YANG De-hua %A WANG Ming-wei %J Acta Pharmacologica Sinica %D 2017 %B 2017 %9 %! W2476 ameliorates β-cell dysfunction and exerts therapeutic effects in mouse models of diabetes via modulation of the thioredoxin-interacting protein signaling pathway %K %X 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 β-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. %U http://www.chinaphar.com/article/view/9633 %V 38 %N 7 %P 1024–1037 %@ 1745-7254