THE CONTROL OF BETA-CELL FUNCTION BY PED GENE: ITS ABNORMALITY IN TYPE 2 DIABETES

Type 2 diabetes may be determined by abnormalities in either a single gene, or, more frequently, in multiple genes. These abnormalities impair glucose metabolism leading to chronic hyperglycemia and the life-threating complications of diabetes. In most affected patients, the gene(s) causing susceptibility to type 2 diabetes is still unknown, however.We have recently shown that the function of the PED gene is commonly increased in type 2 diabetics. In transgenic animal models, this same defect may lead to diabetes by impairing insulin action on adipose tissue and/or insulin secretion by the pancreatic beta-cells. As the mechanism of PED dysregulation of insulin action has been extensively investigated, we will now focus on those responsible for the impaired beta-cell function. In addition, we propose to clarify the relative contribution of the adipose tissue and beta-cell districts to PED-caused derangement in glucose utilization. To accomplish these tasks, we will analyze beta-cell function in genetically modified animals in which PED gene activity is either increased (transgenics) or knocked-down. To define the consequences of PED expression, we will compare major signalling mechanisms controlling beta-cell functions in these in these and in normal animals. We also plan to generate further transgenic mice featuring increased PED gene expression selectively in the adipose tissue or in the beta-cells. Analysis of these animals will reveal which tissue causes deranged glucose utilization when PED gene features abnormally increased function. This new information will enable us, in the future, to devise targeted strategies to correct PED gene defect and to prevent its consequences in individuals with type 2 diabetes.