MicroRNA-24/MODY Gene Regulatory Pathway Mediates Pancreatic Beta-Cell Dysfunction
- Yunxia Zhua,
- Weiyan Youa,
- Hongdong Wanga,
- Yating Lia,
- Nan Qiaoa,
- Yuguang Shid,
- Chenyu Zhangc,
- David Bleichb and
- Xiao Hana,*
- aKey Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Diabetes Center, Nanjing Medical University;
- bUMDNJ-New Jersey Medical School;
- cState Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, P. R. China;
- dDepartment of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, 500 University Drive, H166, Hershey, PA 17033
- *Corresponding author: Xiao Han
Both over-nutrition and genetics contribute separately to pancreatic beta-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 found to be highly expressed in pancreatic beta-cells and further upregulated in islets from genetic fatty (db/db) or high-fat diet fed mice, and islets subject to oxidative stress. Over expression of miR-24 inhibited insulin secretion and beta-cell proliferation, potentially involving 351 down-regulated 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 youth (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 over expression, while restoring their expression rescued beta-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 micro-RNA, miR-24.
- Received January 29, 2013.
- Accepted June 4, 2013.
- © 2013 by the American Diabetes Association.
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