Grant: Project Grant

Our research group established unique methods for simultaneously testing thousands of drugs to identify new chemicals that might be useful for beta-cell protection in diabetes. One of these screens was designed to identify drugs that can protect beta-cells from cytokines that the immune system uses to kill beta-cells in type 1 diabetes. The drugs we tested were specially selected from a library of FDA-approved drugs, meaning that they were already optimized for use in humans. We identified a drug called carbamazepine that reduced beta-cell death in the type 1 diabetes-like context. Carbamazepine is an interesting lead compound because it works by inhibiting a specific type of sodium channels, encoded by the Scn9a gene, but only when they are over-active. This was the first implication of sodium channels in beta-cell death and opened up a whole new area for type 1 diabetes drug discovery. Importantly, pancreatic beta-cells have a unique complement of sodium channels, meaning that this drug and its derivatives are likely to have beta-cell-selective action. We validated our cell culture data by showing that carbamazepine reduces diabetes incidence in the gold standard NOD mouse model. We also determined that carbamazepine can protect human beta-cells. In the proposed studies, we plan to continue this exciting line of investigation towards a new diabetes therapeutic and answer several key questions that arose from our previous studies. First, we must determine how carbamazepine and Scn9a protect the mice from type 1 diabetes. Second, we have to test how carbamazepine and Scn9a affect insulin secretion. Third, we plan to develop and test new analogues of carbamazepine that might have even more favorable properties for a human clinical trial. These studies will show whether beta-cell sodium channels are a viable therapeutic target in diabetes.