Journal Article

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

Ting LI Guang-yao LIN Li ZHONG Yan ZHOU Jia WANG Yue ZHU Yang FENG Xiao-qing CAI Qing LIU Olivier NOSJEAN Jean A BOUTIN Pierre RENARD De-hua YANG Ming-wei WANG

2017

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 3T3-L1 Cells / Adenine - administration & dosage / Adenine - analogs & derivatives / Adenine - chemistry / Adenine - pharmacology / Administration, Oral / Animals / Biomedical and Life Sciences / Biomedicine / 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 / Immunology / Insulin - metabolism / Insulin-Secreting Cells - drug effects / Insulin-Secreting Cells - metabolism / Internal Medicine / Male / Medical Microbiology / Mice / Mice, Inbred C57BL / Molecular Structure / Original / original-article / Pharmacology/Toxicology / Rats / Rats, Sprague-Dawley / Signal Transduction - drug effects / Streptozocin / Structure-Activity Relationship / Thioredoxins - antagonists & inhibitors / Thioredoxins - genetics / Thioredoxins - metabolism / Vaccine / 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