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- Title
Glucolipotoxicity-Inhibited Regulates Pancreatic β-Cell Function and Survival.
- Authors
Qiqing Huang; Weiyan You; Yating Li; Yi Sun; Yuncai Zhou; Yan Zhang; Dechen Liu; Shanshan Zhan; Yunxia Zhu; Xiao Han; Huang, Qiqing; You, Weiyan; Li, Yating; Sun, Yi; Zhou, Yuncai; Zhang, Yan; Liu, Dechen; Zhan, Shanshan; Zhu, Yunxia; Han, Xiao
- Abstract
Inhibition of microRNAs (miRNAs) essential for pancreatic β-cell biology (e.g., miR-375) results in β-cell failure and diabetes in rodent models. Whether the downregulation of miRNAs in pancreatic islets is involved in the development of human type 2 diabetes remains unclear. Here, with the use of an miRNA microarray, we identified a set of miRNAs that were differentially expressed in healthy human islets under glucolipotoxic conditions. A downregulated miRNA, miR-299-5p, was preferentially studied because its inhibition causes dramatic β-cell dysfunction and apoptosis. Proteomic profiling and bioinformatics methods identified four target genes, including a Trp53 effector, Perp, that were further confirmed by luciferase reporter assays. We narrowed down the effector of miR-299-5p downregulation to PERP owing to its upregulation in islets from diabetic rodents. Indeed, Perp inhibition prevented the β-cell impairment caused by either miR-299-5p reduction or glucolipotoxicity. Additional investigations confirmed the modulatory effect of PERP on insulin secretion. Collectively, miR-299-5p appears to be an essential regulator of β-cell biology, and its downregulation links PERP enhancement to β-cell dysfunction and apoptosis in glucolipotoxic settings. Our work demonstrates a novel mechanism of glucolipotoxicity-induced β-cell failure mediated through miR-299-5p downregulation.
- Subjects
MICRORNA; GENE expression; CELL proliferation; APOPTOSIS; PANCREATIC beta cells; RNA metabolism; ANIMAL experimentation; CELL lines; CELL physiology; COMPARATIVE studies; ISLANDS of Langerhans; RESEARCH methodology; MEDICAL cooperation; MICE; RATS; RESEARCH; RNA; EVALUATION research
- Publication
Diabetes, 2018, Vol 67, Issue 11, p2280
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db18-0223