TY - JOUR AU - LI Ting AU - LIN Guang-yao AU - ZHONG Li AU - ZHOU Yan AU - WANG Jia AU - ZHU Yue AU - FENG Yang AU - CAI Xiao-qing AU - LIU Qing AU - NOSJEAN Olivier AU - BOUTIN Jean A AU - RENARD Pierre AU - YANG De-hua AU - WANG Ming-wei PY - 2017 TI - W2476 ameliorates β-cell dysfunction and exerts therapeutic effects in mouse models of diabetes via modulation of the thioredoxin-interacting protein signaling pathway JF - Acta Pharmacologica Sinica; Vol 38, No 7 (July 2017): Acta Pharmacologica Sinica Y2 - 2017 KW - N2 - 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. UR - http://www.chinaphar.com/article/view/9633