Substantial β‐cell failure occurs at the early stage of T2DM32 and serves as a major contributing factor of the pathogenesis of T2DM.33 In this study, we demonstrated that FGF21 expression was decreased dramatically in pancreatic islets of db/db mice and that pancreatic islet‐specific overexpression of FGF21 by AAV‐FGF21 significantly improved glycolipid metabolism and alleviated the development of diabetes in db/db mice. This evidence concerns the gene FGF21 and diabetes mellitus.