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

Abstract：

: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 TXNIP-regulated signaling pathway might present a viable approach to manage diabetes.

journal_name

Acta Pharmacol Sin

journal_title

Acta pharmacologica Sinica

authors

Li T,Lin GY,Zhong L,Zhou Y,Wang J,Zhu Y,Feng Y,Cai XQ,Liu Q,Nosjean O,Boutin JA,Renard P,Yang DH,Wang MW

doi

10.1038/aps.2017.15

subject

Has Abstract

pub_date

2017-07-01 00:00:00

pages

1024-1037

issue

eissn

1671-4083

issn

1745-7254

pii

aps201715

journal_volume

pub_type

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