Perilipin2 Down-Regulation in Β Cells Impairs Insulin Secretion under Nutritional Stress and Damages Mitochondria

Perilipin 2 (PLIN2) is a lipid droplet (LD) protein in beta cells that increases under nutritional stress. Downregulation of PLIN2 is often sufficient to reduce LD accumulation. To determine whether PLIN2 positively or negatively affects beta cell function under nutritional stress, PLIN2 was downregulated in mouse beta cells, INS1 cells, and human islet cells. beta Cell-specific deletion of PLIN2 in mice on a high-fat diet reduced glucose-stimulated insulin secretion (GSIS) in vivo and in vitro. Downregulation of PLIN2 in INS1 cells blunted GSIS after 24-hour incubation with 0.2 mM palmitic acid. Downregulation of PLIN2 in human pseudoislets cultured at 5.6 mM glucose impaired both phases of GSIS, indicating that PLIN2 is critical for GSIS. Downregulation of PLIN2 decreased specific OXPHOS proteins in all 3 models and reduced oxygen consumption rates in INS1 cells and mouse islets. Moreover, we found that PLIN2-deficient INS1 cells increased the distribution of a fluorescent oleic acid analog to mitochondria and showed signs of mitochondrial stress, as indicated by susceptibility to fragmentation and alterations of acyl-carnitines and glucose metabolites. Collectively, PLIN2 in beta cells has an important role in preserving insulin secretion, beta cell metabolism, and mitochondrial function under nutritional stress.