Our work provides direct evidence that Hippo pathway’s central kinase LATS2 is activated under diabetogenic conditions, which induced β-cell failure through increased β-cell apoptosis and impaired β-cell function, while LATS2’s inactivation resulted in resistance to β-cell apoptosis, improved glycemia, insulin secretion and β-cell mass in in vitro, ex vivo and in vivo experimental models of diabetes. The gene discussed is LATS2; the disease is diabetes mellitus.