We report for the first time that: (1) Phlda3 is upregulated in islets of diabetic rodents and humans; (2) Phlda3 expression is induced in response to the major stress conditions associated with beta cell failure in diabetes, namely inflammatory, ER and oxidative stress; and (3) Phlda3 plays an important adaptive role to protect against beta cell death during stress (Fig. 9). This evidence concerns the gene PHLDA3 and diabetes mellitus.