β-Cell-specific inactivation of the mouseIpf1/Pdx1 gene results in loss of the β-cell phenotype and maturity onset diabetes

Abstract

To study the late ␤-cell-specific function of the homeodomain protein IPF1/PDX1 we have generated mice in which the Ipf1/Pdx1 gene has been disrupted specifically in ␤ cells. These mice develop diabetes with age, and we show that IPF1/PDX1 is required for maintaining the ␤ cell identity by positively regulating insulin and islet amyloid polypeptide expression and by repressing glucagon expression. We also provide evidence that IPF1/PDX1 regulates the expression of Glut2 in a dosage-dependent manner suggesting that lowered IPF1/ PDX1 activity may contribute to the development of type II diabetes by causing impaired expression of both Glut2 and insulin.

Pancreas organogenesis: From bud to plexus to gland

“…5). The success of this mixture is likely explained by the respective TF activities: (1) Ngn3 aids acquisition of general endocrine competence; (2) Pdx1 helps establish a stable b-cell rather than other endocrine fates; (3) MafA augments Pdx1 function, but pushes the newly generated b-cell towards achieving the final mature, functional state Ahlgren et al, 1998;Gradwohl et al, 2000;Vanhoose et al, 2008). The reported induction of b-cells was sporadic, apparently occurring directly from the acinar state without replication or movement through a prolonged dedifferentiated state.…”

A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

“…The sand rat (Psammomys obesus) is a particularly an interesting case, as Pdx1 is not normally found in islets from these animals; however, gene transfer experiments show that repletion of Pdx1 in these islets greatly enhances insulin content and glucose-stimulated insulin transcription [62]. Complete or near-complete deletion of Pdx1 in late embryonic [63] or adult mice [64] also result in a later diabetic phenotype. Although subtle developmental defects cannot be ruled out, these observations suggest a dramatically different requirement for Pdx1 gene dosage in the developing pancreas vs. the mature β cell, the latter of which may require more tightly regulated transcription and/or translation.…”

“…Based upon these studies, several mechanisms have been postulated: (a) increased β cell apoptosis via and Bcl-2), with resulting loss of downregulation of anti-apoptotic genes (Bcl XL functional cell mass [56,67], (b) loss of activity of key Pdx1 target genes whose products are involved in glucose-stimulated insulin transcription and secretion (including Glut2, glucokinase, MafA, Nkx6.1, insulin) [57,63,[68][69][70][71][72][73][74][75][76], and (d) loss of new β cell formation/regeneration [64,77]; in this regard, studies suggest that the action of glucagon-like peptide 1 (GLP1) in enhancing β cell growth and formation in the adult may rely upon activation of Pdx1 in β cells and potential precursor cell types, such as those residing within ducts [74,[78][79][80][81][82].…”

“…These included the genes encoding insulin [68,70,71,126], Glut2 [127,128], glucokinase [129,130], islet amyloid polypeptide (IAPP) [63,75,131,132], Pax4 [133], Nkx6.1 [69,134], MafA [72], liver receptor homolog (Lrh) 1 [135], and Pdx1 itself [37]. In recent years, the direct regulation of many of these genes by Pdx1 has been confirmed using loss-of-function studies in islets and intact animals, and occupancy by Pdx1 of the endogenous genes in islets and β cell lines has been confirmed using the chromatin immunoprecipitation (ChIP) assay [70].…”

“…Although the majority of these cofactor interactions with Pdx1 are believed to enhance the activation function of Pdx1, there is the distinct possibility that certain cofactor interactions may allow Pdx1 to aid in the repression of some genes. In this regard, the well-defined repression of genes such as glucagon [63,64,70,134] and K19 [100] by Pdx1 may reflect a repression complex formed in association with corepressor molecules.…”