| First Author | Regué L | Year | 2021 |
| Journal | Mol Metab | Volume | 48 |
| Pages | 101209 | PubMed ID | 33705986 |
| Mgi Jnum | J:317171 | Mgi Id | MGI:6714924 |
| Doi | 10.1016/j.molmet.2021.101209 | Citation | Regue L, et al. (2021) RNA m6A reader IMP2/IGF2BP2 promotes pancreatic beta-cell proliferation and insulin secretion by enhancing PDX1 expression. Mol Metab 48:101209 |
| abstractText | BACKGROUND: Type 2 diabetes (T2D) is a common metabolic disease. Variants in human IGF2 mRNA binding protein 2 (IMP2/IGF2BP2) are associated with increased risk of T2D. IMP2 contributes to T2D susceptibility primarily through effects on insulin secretion. However, the underlying mechanism is not known. METHODS: To understand the role of IMP2 in insulin secretion and T2D pathophysiology, we generated Imp2 pancreatic beta-cell specific knockout mice (betaIMP2KO) by recombining the Imp2(flox) allele with Cre recombinase driven by the rat insulin 2 promoter. We further characterized metabolic phenotypes of betaIMP2KO mice and assessed their beta-cell functions. RESULTS: The deletion of IMP2 in pancreatic beta-cells leads to reduced compensatory beta-cell proliferation and function. Mechanically, IMP2 directly binds to Pdx1 mRNA and stimulates its translation in an m6A dependent manner. Moreover, IMP2 orchestrates IGF2-AKT-GSK3beta-PDX1 signaling to stable PDX1 polypeptides. In human EndoC-betaH1 cells, the over-expression of IMP2 is capable to enhance cell proliferation, PDX1 protein level and insulin secretion. CONCLUSION: Our work therefore reveals IMP2 as a critical regulator of pancreatic beta-cell proliferation and function; highlights the importance of posttranscriptional gene expression in T2D pathology. |
