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.
Fujimoto
K
K
Department of Internal Medicine, Washington University School of Medicine/Barnes-Jewish Hospital, St Louis, MO, USA.
Polonsky
K S
KS
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000378:metabolism*; D001343:Autophagy; D002452:Cell Count; D002470:Cell Survival / Q000502:physiology; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D015534:Trans-Activators / Q000172:deficiency / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D018398:Homeodomain Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein