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

Area of Science:

• Endocrinology
• Molecular Biology
• Metabolic Diseases

Background:

• Type 2 diabetes (T2D) is a prevalent metabolic disorder.
• Genetic variants in IGF2 mRNA binding protein 2 (IMP2/IGF2BP2) are linked to increased T2D risk.
• IMP2's role in insulin secretion and T2D pathogenesis requires elucidation.

Purpose of the Study:

• To investigate the precise mechanism by which IMP2 influences insulin secretion.
• To determine the role of IMP2 in pancreatic beta-cell function and proliferation.
• To understand IMP2's contribution to T2D pathophysiology.

Main Methods:

• Generation of Imp2 pancreatic beta-cell specific knockout mice (βIMP2KO).
• Characterization of metabolic phenotypes and beta-cell functions in βIMP2KO mice.
• Assessment of IMP2's direct binding to Pdx1 mRNA and its effect on translation in human EndoC-βH1 cells.

Main Results:

• Deletion of IMP2 in beta-cells impaired compensatory proliferation and function.
• IMP2 directly binds Pdx1 mRNA, enhancing its translation in an m6A-dependent manner.
• IMP2 regulates the IGF2-AKT-GSK3β-PDX1 signaling pathway, stabilizing PDX1 protein.

Conclusions:

• IMP2 is identified as a critical regulator of pancreatic beta-cell proliferation and function.
• The study underscores the significance of posttranscriptional gene regulation in T2D.
• IMP2's role in enhancing PDX1 levels and insulin secretion was confirmed in human cells.