Final Report Summary - ISLETVASC (Molecular Mechanisms Regulating Pancreatic Islet Vascularization)
Diabetes has emerged as one of the leading global health threats with a projected burden on public health that appears interminable. To date, numerous counter-regulatory mechanisms have been characterized in the cell illustrating the dynamic nature of the intracellular environment. Among the more recently discovered is the microRNA (miRNA) pathway and advances in the field have improved our understanding of how these small RNAs integrate into the already complex landscape of regulating gene expression. Our project focused on the functional role of miRNAs in the pancreatic beta cell and established their role in the compensatory proliferation of this cell type during insulin resistance. In addition to developing new genetic mouse models, state of the art proteomic and lipidomic analysis helped to elucidate how miRNAs regulate the release of insulin and other functional molecules. While many of these systemic factors remain uncharacterized, they highlight the complex role of the beta cell in regulating energy homeostasis. In addition to the vascular and neuronal cell types which contribute to the architecture of the pancreatic islet, the identification of the beta cell secretome suggests a vast potential for intercellular crosstalk. Future studies now aim to establish whether these factors released by the beta cell are essential to the maintenance of glucose and energy metabolism and to determine how they may contribute to the development of therapeutic strategies to prevent the prevalence of diabetes and its related disorders. These findings culminate over 10 years since our initial study which identified miR-375, a miRNA now established among the highest expressed sequences in the beta cell.