PREP1 GENE FUNCTION IN TYPE 2 DIABETES

Important information has been gathered over the past years concerning the identity of genes responsible for type 2 diabetes (T2D) susceptibility. These studies already proved to be helpful in uncovering novel biological mechanisms amenable to therapeutic manipulation, in guiding better drug use in certain forms of diabetes and also evidenced that many more risk genes remain to be identified. The work proposed in the present application aims at testing the significance to T2D of a previously unrecognized gene, termed PREP1, whose function in controlling glucose metabolism has recently been discovered in my laboratory. Based on this work, we already know that PREP1 gene function is increased in T2D individuals and in their euglycemic offspring, and that this defect causes insulin-resistance in muscle cells in vitro. Consistently, mice with reduced Prep1 function feature enhanced sensitivity to insulin and protection from diabetes. Using well characterized study groups (available for this work), we will now clarify whether the increased function of PREP1 associates to specific T2D features such as the impaired insulin secretion and action. We will then analyze PREP1 gene variants to determine the causes of the increased PREP1 function observed in T2D. In a different arm of the study, we will generate genetically modified mouse models featuring increased PREP1 function either systemically or in skeletal muscle, a major target of insulin action. These models, in combination with in vitro experiments, will be instrumental to understand, at the mechanistic level, how PREP1 excess impairs the insulin regulatory function on glucose metabolism, and whether this is the consequence of PREP1 activity on insulin production in addition to that on insulin action. This work may identify PREP1 as a novel T2D risk gene and uncover new potential pharmacological targets for T2D treatment.