Here, we determined that small molecule, 5-chloro-N-[4-chloro-3-(trifluoromethyl)phenyl]thiophene-2-sulfonamide (FX5, Figure 1A), as a non-steroidal GR inhibitor effectively reduced gluconeogenesis and improved glucose homeostasis in db/db and HFD/STZ-induced T2DM mice. Here, NR3C1 is linked to type 2 diabetes mellitus.