Pdx1 and other factors that regulate pancreatic beta-cell survival.

A progressive reduction in beta-cell mass occurs in the evolution of diabetes. Thus understanding the mechanisms responsible for this reduction in beta-cell mass is important for understanding the pathogenesis of diabetes and in developing novel approaches to prevention and treatment. Pancreatic duodenal homeobox 1 (Pdx1) is a transcription factor that plays a central role in pancreatic beta-cell function and survival. Complete deficiency of Pdx1 is associated with pancreatic agenesis, and partial deficiency leads to severe beta-cell dysfunction, and increases beta-cell death and diabetes both in rodent and human. Chronic hyperglycaemia and dyslipidaemia, which are major features of type 2 diabetes, cause beta-cell dysfunction via reduced Pdx1 expression. Inhibition of insulin/insulin-like growth factor (Igf) signalling followed by reduced Pdx1 expression is a common pathway induced by the majority of the mechanisms in apoptotic beta-cells. Although the report so far paid little attention to non-apoptotic beta-cell death (autophagy and necrosis), we expect these are also involved in the pathogenesis of diabetes. The potential role of Pdx1 in non-apoptotic beta-cell death should also be considered in future studies in diabetes, and in attempts to develop novel agents that target this process for prevention and treatment of the disorder.