Adenosine kinase inhibition selectively promotes rodent and porcine islet β-cell replication

Diabetes is a pathological condition characterized by relative insulin deficiency, persistent hyperglycemia, and, consequently, diffuse micro-and macrovascular disease. One therapeutic strategy is to amplify insulin-secretion capacity by increasing the number of the insulin-producing beta cells without triggering a generalized proliferative response. Here, we present the development of a small-molecule screening platform for the identification of molecules that increase beta-cell replication. Using this platform, we identify a class of compounds [ adenosine kinase inhibitors (ADK-Is)] that promote replication of primary beta cells in three species (mouse, rat, and pig). Furthermore, the replication effect of ADK-Is is cell type-selective: treatment of islet cell cultures with ADK-Is increases replication of beta cells but not that of alpha cells, PP cells, or fibroblasts. Short-term in vivo treatment with an ADK-I also increases beta-cell replication but not exocrine cell or hepatocyte replication. Therefore, we propose ADK inhibition as a strategy for the treatment of diabetes.