In summary, our findings demonstrate that pancreatic FGF21 protects β‐cells from T2DM‐induced injury through promoting insulin synthesis and secretion, which are mediated by PI3K/Akt signaling‐dependent up‐regulation of MafA, MafB and PDX‐1 as well as SNARE proteins. Here, MAFB is linked to type 2 diabetes mellitus.