Glucolipotoxicity-Inhibited miR-299-5p Regulates Pancreatic beta-Cell Function and Survival

Inhibition of microRNAs (miRNAs) essential for pancreatic beta-cell biology (e.g., miR-375) results in beta-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 beta-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 beta-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 beta-cell biology, and its downregulation links PERP enhancement to beta-cell dysfunction and apoptosis in glucolipotoxic settings. Our work demonstrates a novel mechanism of glucolipotoxicity-induced beta-cell failure mediated through miR-299-5p downregulation.