Pleomorphic adenoma gene-like 1 (PLAGL1) has been linked to transient neonatal diabetes mellitus. Here, we investigated the role of the related pleomorphic adenoma gene 1 (PLAG1) in glucose homeostasis. Our results show that PLAG1 is involved in the regulation of β-cell neogenesis, a process that is crucial for the development of diabetes. The findings of this study provide new insights into the molecular mechanisms underlying β-cell neogenesis and highlight the potential of PLAG1 as a therapeutic target for the treatment of diabetes.