RNA m6A reader IMP2/IGF2BP2 promotes pancreatic ß-cell proliferation and insulin secretion by enhancing PDX1 expression.
Mol Metab
; 48: 101209, 2021 06.
Article
in En
| MEDLINE
| ID: mdl-33705986
ABSTRACT
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 ß-cell specific knockout mice (ßIMP2KO) by recombining the Imp2flox allele with Cre recombinase driven by the rat insulin 2 promoter. We further characterized metabolic phenotypes of ßIMP2KO mice and assessed their ß-cell functions.RESULTS:
The deletion of IMP2 in pancreatic ß-cells leads to reduced compensatory ß-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-GSK3ß-PDX1 signaling to stable PDX1 polypeptides. In human EndoC-ßH1 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 ß-cell proliferation and function; highlights the importance of posttranscriptional gene expression in T2D pathology.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
RNA, Messenger
/
Signal Transduction
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Trans-Activators
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Adenosine
/
RNA-Binding Proteins
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Homeodomain Proteins
/
Cell Proliferation
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Diabetes Mellitus, Type 2
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Insulin-Secreting Cells
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Insulin Secretion
Type of study:
Prognostic_studies
Limits:
Animals
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Humans
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Male
/
Middle aged
Language:
En
Journal:
Mol Metab
Year:
2021
Document type:
Article
Affiliation country:
United States