Pdx1 and other factors that regulate pancreatic beta-cell survival

Abstract

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.

Figure. Insulin/Igf signaling in β-cell

Insulin and Igf bind to insulin receptor and Igf receptor, respectively followed by phosphorylation of Irs1/Irs2. This promotes the activation of Akt in a PI3K-dependent fashion, resulting in inactivation of Gsk-3β and Foxo1. Gsk-3β and Foxo1 decrease Pdx1 expression at protein and transcription level, respectively. Akt can also directly regulate Pdx1 function. Ins; insulin, Igf; insulin-like growth factor, Ir; insulin receptor, Igfr; Igf receptor; Irs; insulin receptor substrate, PI3K; phosphatidylinositol 3-kinase, Gsk-3β; glycogen synthase kinase-3β, Foxo1; forkhead box o 1, Pdx1; pancreatic duodenal homeobox 1.