<i>GDF15</i>plays a critical role in insulin secretion in INS-1 cells and human pancreatic islets

Abstract

Mounting evidence points to a link between growth differentiation factor-15 (<i>GDF15</i>) expression and the onset and progression of diabetes mellitus. However, the exact role of <i>GDF15</i> in pancreatic β-cell function is unclear. To examine the role of <i>GDF15</i> in β-cell function, bioinformatics analysis and functional experiments involving <i>GDF15</i> silencing and overexpression were performed in INS-1 cells and human islets. Public microarray and RNA-seq expression data showed that islets obtained from diabetic donors express high levels of <i>GDF15</i> compared to islets obtained from normal donors. Moreover, analysis of RNA-seq expression data revealed that <i>GDF15</i> expression correlates positively with that of insulin (<i>INS</i>), <i>KCNJ11</i>, <i>GLUT1</i>, <i>MAFA</i>, <i>INSR</i> and negatively with that of Glucokinase (<i>GCK</i>) and Alpha-Ketoglutarate Dependent Dioxygenase (<i>FTO</i>). No T2D-associated genetic variants in the <i>GDF15</i> were found to pass genome-wide significance in the TIGER portal. Expression silencing of <i>Gdf15</i> in INS-1 cells reduced insulin release, glucose uptake levels, increased reactive oxygen species (ROS) production and apoptosis levels. While <i>Gdf15</i>-silenced cells downregulated mRNA expression of <i>Ins</i>, <i>Pdx1</i>, <i>Mafa</i>, and <i>Glut2</i> genes, its overexpression human islets was associated with increased insulin secretion and upregulated expression of MAFA and GLUT1 but not INS or GCK. Silencing of <i>Pdx1</i> or <i>Mafa</i> in INS-1 cells did not affect the expression of GDF15. These findings suggest that <i>GDF15</i> plays a significant role in pancreatic β-cell function.