RNA m6A reader IMP2/IGF2BP2 promotes pancreatic β-cell proliferation and insulin secretion by enhancing PDX1 expression.

Abstract Type 2 diabetes (T2D) is a common metabolic disease. Variants in IMP2 (IGF2BP2) associated with increased risk of T2D impair insulin secretion. However, the underlying mechanism is not known. IMP2 is an RNA binding protein that preferentially recognize N6-methyladenosine (m6A) modified mRNAs. Here we report that the deletion of IMP2 in pancreatic β-cells leads to reduced compensatory β-cell proliferation and function in mice. Mechanically, IMP2 directly binds to Pdx1 mRNA and stimulates its translation in a m6A dependent manner. In addition, IMP2 also orchestrates IGF2-AKT-GSK3-PDX1 signaling to promotes insulin secretion. In human EndoC-βH1 cells, the expression of IMP2 is capable to enhance cell proliferation, PDX1 expression, IGF2 signaling as well as insulin secretion. Our work therefore reveals IMP2 as a critical regulator of β-cell function and highlights the importance of posttranscriptional gene expression in T2D pathology.