TSPA as a novel ATF6α translocation inducer efficiently ameliorates insulin sensitivity restoration and glucose homeostasis in db/db mice

Activating transcription factor 6 alpha (ATF6 alpha) as a transducer in unfolded protein response (UPR), plays an important role in liver glucose metabolism and insulin resistance. Thus, targeting ATF6 alpha activation has been proposed to be a potential strategy for anti-T2DM drug discovery. Here, we determined that small molecule 2-15-[1-(4-chlorophenoxy)ethyl]-4-pheny1-4H-1,2,4-triazol-3-yl]sulfanyl-N-(1,5-dimethy1-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)acetamide (TSPA) functioned as an ATF6 alpha translocation inducer effectively promoting ATF6 alpha translocation into nucleus and ameliorating glucose homeostasis on db/db mice. TSPA promoted ATF6 alpha translocation into nucleus without incresing C/EBP-homologous protein (CHOP) expression. TSPA restored the tunicamycin (TM)-stimulated insulin receptor (IR) desensitization through ATF6 alpha activation, inhibited gluconeogenesis and efficiently improved glucose homeostasis on db/db mice. Furthermore, TSPA protected insulin pathway involving p38/X-box binding protein 1s (Xbp1s)/ER chaperones signaling pathway. Our current study has determined that ATF6 alpha was a promising therapeutic target and also highlighted the potential of TSPA in the treatment of type 2 diabetes mellitus (T2DM). (C) 2018 Elsevier Inc. All rights reserved.