Abstract

In type 1 diabetes, the insulin-producing beta-cells in the pancreas are destroyed by the immune system, resulting in aberrantly high blood glucose levels. Unlike many other cells in the body, pancreatic beta-cells divide infrequently, which limits the ability of beta-cells to regenerate after beta-cell loss. There has been considerable interest in understanding the mechanisms that regulate the proliferation of beta-cells with the goal of discovering new therapeutic targets to promote beta-cell regeneration. However, only a few molecules that can increase the proliferation of human beta-cells have been identified. Given that most molecules that stimulate the proliferation of beta-cells also have pro-proliferative effects in other tissues, systemic administration of drugs against such molecules imposes a significant cancer risk. Therefore, beta-cell-specific inhibition would be the preferred therapeutic approach.

The goal of the proposed work is to conduct proof-of-principle studies for beta-cell-directed therapies aimed at expanding beta-cell mass in diabetic patients. We recently discovered that pharmacological inhibition of a protein deacetylase significantly increases beta-cell proliferation in both mouse and human pancreatic islets. Importantly, inhibition of this deacetylase does not cause beta-cell death, beta-cell tumors, or beta-cell dysfunction indicating that targeting this molecule in beta-cells could be a way to safely increase beta-cells mass. The objective of this study is to employ a new beta-cell-directed targeting strategy developed by Ionis Pharmaceuticals to inhibit this deacetylase selectively in beta-cells. If successful, results of these experiments could pave the way for trials in humans, testing whether beta-cell mass can be expanded using this approach.