期刊
MOLECULAR METABOLISM
卷 48, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.molmet.2021.101209
关键词
IMP2; IGF2BP2; T2D; Insulin secretion; m6A; Post-transcriptional gene expression regulation
资金
- NIH [DK17776, DK057521]
- MGH institutional funds
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/).
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