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

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 13-cell specific knockout mice (13IMP2KO) by recombining the Imp2f iota ox allele with Cre recombinase driven by the rat insulin 2 promoter. We further characterized metabolic phenotypes of 13IMP2KO mice and assessed their 13-cell functions. Results: The deletion of IMP2 in pancreatic 13-cells leads to reduced compensatory 13-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-GSK313-PDX1 signaling to stable PDX1 polypeptides. In human EndoC-13H1 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 13-cell proliferation and function; highlights the importance of posttranscriptional gene expression in T2D pathology. (c) 2021 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).