Mechanisms of β cell failure in the pathogenesis of Type 2 diabetes

β cell failure plays a key role in the pathogenesis of type 2 diabetes. It consists of impaired insulin secretion and decreased β cell mass. Recent insight into the pathogenesis of diabetes‐associated β cell failure has shown that (1) β cell compensation to insulin resistance occurs primarily via increased β cell replication; (2) commonly employed diabetes treatments are associated with a seemingly irreversible loss of β cell function; and (3) most diabetes‐associated genes identified in recent genome‐wide association studies appear to regulate β cell mass and/or function, as opposed to insulin action. Experimental studies in animal models have contributed to establishing the idea that pancreatic β cells are an “insulin target tissue,” in which insulin signaling links insulin secretion with cellular proliferation and survival. It is possible that β cell failure represents but another aspect of insulin resistance. Prevention of β cell dysfunction is a critical goal of diabetes therapy, and it will require the identification of “druggable” cellular pathways that can be enlisted in the clinic to achieve durability of treatment. Drug Dev Res 69:111–115, 2008 © 2008 Wiley‐Liss, Inc.