W2476 ameliorates β-cell dysfunction and exerts therapeutic effects in mouse models of diabetes via modulation of the thioredoxin-interacting protein signaling pathway

• Published in: Acta pharmacologica Sinica Vol. 38; no. 7; pp. 1024 - 1037
• Main Authors: Li, Ting, Lin, Guang-Yao, Zhong, Li, Zhou, Yan, Wang, Jia, Zhu, Yue, Feng, Yang, Cai, Xiao-Qing, Liu, Qing, Nosjean, Olivier, Boutin, Jean A, Renard, Pierre, Yang, De-Hua, Wang, Ming-Wei
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.07.2017
• Subjects: 3T3-L1 Cells; Adenine - administration & dosage; Adenine - analogs & derivatives; Adenine - chemistry; Adenine - pharmacology; Administration, Oral; Animals; Carrier Proteins - antagonists & inhibitors; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cells, Cultured; Diabetes Mellitus, Experimental - chemically induced; Diabetes Mellitus, Experimental - drug therapy; Disease Models, Animal; Dose-Response Relationship, Drug; Insulin - metabolism; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Male; Mice; Mice, Inbred C57BL; Molecular Structure; Original; Rats; Rats, Sprague-Dawley; Signal Transduction - drug effects; Streptozocin; Structure-Activity Relationship; Thioredoxins - antagonists & inhibitors; Thioredoxins - genetics; Thioredoxins - metabolism; β细胞; 信号通路; 小鼠模型; 治疗作用; 硫氧还蛋白; 糖尿病; 蛋白相互作用; 调制器
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/aps.2017.15

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-IE 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 pmol/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-IE 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 TXNIP- regulated signaling pathway might present a viable approach to manage diabetes.