title: MicroRNA-24/MODY gene regulatory pathway mediates pancreatic β-cell dysfunction.
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.
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Diabetes Center, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China.
authors.forename: Yunxia
authors.initials: Y
authors.lastname: Zhu
authors.forename: Weiyan
authors.initials: W
authors.lastname: You
authors.forename: Hongdong
authors.initials: H
authors.lastname: Wang
authors.forename: Yating
authors.initials: Y
authors.lastname: Li
authors.forename: Nan
authors.initials: N
authors.lastname: Qiao
authors.forename: Yuguang
authors.initials: Y
authors.lastname: Shi
authors.forename: Chenyu
authors.initials: C
authors.lastname: Zhang
authors.forename: David
authors.initials: D
authors.lastname: Bleich
authors.forename: Xiao
authors.initials: X
authors.lastname: Han
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000502:physiology; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: C543845:MIRN24 microRNA, human; D035683:MicroRNAs; C529080:Mirn24 microRNA, mouse