期刊
ACTA PHARMACOLOGICA SINICA
卷 38, 期 7, 页码 1024-1037出版社
ACTA PHARMACOLOGICA SINICA
DOI: 10.1038/aps.2017.15
关键词
diabetes; glucose; TXNIP; beta-cells; W2476; high-throughput screening
资金
- National Health and Family Planning Commission [2012ZX09304-011, 2013ZX09401003-005, 2013ZX09507001, 2013ZX09507002]
- Shanghai Science and Technology Development Fund [15DZ2291600, 14431901200]
- Ministry of Science and Technology International Cooperation Program [2014DFG32200]
- Les Laboratories Servier (France)
- Thousand Talents Program in China
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 beta-cells. Overexpression of txnip not only induces beta-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-)denine], 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 mu mol/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 beta-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.
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