Abstract
Overnutrition and genetics both contribute separately to pancreatic β-cell dysfunction, but how these factors interact is unclear. This study was aimed at determining whether microRNAs (miRNAs) provide a link between these factors. In this study,
miRNA-24
(
miR-24
) was highly expressed in pancreatic β-cells and further upregulated in islets from genetic fatty (
db
/
db
) or mice fed a high-fat diet, and islets subject to oxidative stress. Overexpression of
miR-24
inhibited insulin secretion and β-cell proliferation, potentially involving 351 downregulated genes. By using bioinformatic analysis combined with luciferase-based promoter activity assays and quantitative real-time PCR assays, we identified two maturity-onset diabetes of the young (MODY) genes as direct targets of
miR-24.
Silencing either of these MODY genes (
Hnf1a
and
Neurod1
) mimicked the cellular phenotype caused by
miR-24
overexpression, whereas restoring their expression rescued β-cell function. Our findings functionally link the
miR-24
/MODY gene regulatory pathway to the onset of type 2 diabetes and create a novel network between nutrient overload and genetic diabetes via
miR-24
.