Here, we discovered that small molecule, 5-chloro-N-[4-chloro-3-(trifluoromethyl)phenyl]thiophene-2-sulfonamide (FX5) as a new non-steroidal GR antagonist efficiently ameliorated glucose homeostasis in db/db and HFD/STZ-induced T2DM mice. This evidence concerns the gene NR3C1 and type 2 diabetes mellitus.