Grant: Project Grant

Our research group established innovative methods for simultaneously testing thousands of drugs to identify drugs that might be useful to protect insulin secreting beta cells in diabetes. One of these screens identified drugs that can protect beta cells from immune attack in type 1 diabetes. The drugs we tested were selected from a library of FDA-approved drugs, meaning that they were already optimized for use in people. We identified a drug called carbamazepine that reduced beta cell death in a type 1 diabetes context. Carbamazepine is an interesting lead compound because it works by inhibiting a specific type of sodium channel, made by the Scn9a gene, but only when they are highly active. This was the first evidence that sodium channels are important in beta cell survival and opened a new area for type 1 diabetes drug development. Importantly, pancreatic beta cells have a specialized complement of sodium channels, meaning that this drug and its derivatives are likely to be relatively beta cell-selective. We confirmed 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 lab. In the proposed studies, we plan to continue this exciting line of investigation towards a new diabetes drug and answer several key questions that arose from our previous studies. First, we need to understand exactly how carbamazepine and Scn9a affect the activity of the beta cells. Second, we must determine how carbamazepine and Scn9a protect beta cells in the context of type 1 diabetes. Third, we need to study how beta cell sodium channels may modulate local immunity to slow type 1 diabetes. These studies will help us determine whether beta cell sodium channels are a viable therapeutic target in type 1 diabetes.