Glucolipotoxicity-Inhibited <i>miR-299-5p</i> Regulates Pancreatic β-Cell Function and Survival

Abstract

Inhibition of microRNAs (miRNAs) essential for pancreatic β-cell biology (e.g., <i>miR-375</i>) 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, <i>miR-299-5p</i>, 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, <i>Perp</i>, that were further confirmed by luciferase reporter assays. We narrowed down the effector of <i>miR-299-5p</i> downregulation to PERP owing to its upregulation in islets from diabetic rodents. Indeed, <i>Perp</i> inhibition prevented the β-cell impairment caused by either <i>miR-299-5p</i> reduction or glucolipotoxicity. Additional investigations confirmed the modulatory effect of PERP on insulin secretion. Collectively, <i>miR-299-5p</i> 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 <i>miR-299-5p</i> downregulation.