Grant: Operating Grant

The secretion of insulin by the beta-cells of the pancreas is a tightly controlled process that enables the maintenance of blood glucose levels within a very narrow range. Abnormalities in these control mechanisms cause type 2 diabetes, a disease affecting over 2 million Canadians. One of the therapeutic approaches to treat type 2 diabetes consists of increasing the secretion of insulin by the beta-cell with pharmacological compounds. The prerequisite to developing such novel compounds is to understand the molecular and cellular events that regulate the secretion of insulin, so that new drug targets can be identified. The cell surface receptor GPR40 is present on the beta-cell plasma membrane and binds fatty acids. Binding of fatty acids to GPR40 enhances insulin secretion, suggesting that it could represent a novel drug target. However, the mechanisms by which fatty acid binding to the receptor augment the secretion of insulin are still poorly understood. The objective of this proposal is to better define the role of GPR40 in the regulation of insulin secretion. First, we will examine how expression of the receptor is regulated by glucose and fatty acids. Second, we will attempt to identify the cascade of intracellular signals that is activated upon binding of fatty acids to the receptor. Third, we will characterize the mechanisms by which this receptor stimulates insulin secretion. This work will be carried out by using a combination of experimental approaches, including the use of pharmacological agents, molecular tools, and genetic mouse models. By contributing to the understanding of the mechanisms of action of GPR40 and its role in the regulation of insulin secretion, this project will help identify novel drug targets for the treatment of type 2 diabetes.