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Gene Review

Pdx1  -  pancreatic and duodenal homeobox 1

Rattus norvegicus

Synonyms: IDX-1, IPF-1, Idx1, Insulin promoter factor 1, Ipf1, ...
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Disease relevance of Pdx1

  • Differential expression of the insulin gene transcriptional repressor CCAAT/enhancer-binding protein beta and transactivator islet duodenum homeobox-1 in rat pancreatic beta cells during the development of diabetes mellitus [1].
  • Concomitant with a downregulation of IDX-1 and insulin expression, C/EBPbeta is upregulated in association with the manifestation of hyperglycemia during the development of diabetes in the Zucker diabetic fatty (fa/fa) rat and in the 90% pancreatectomy rat model of diabetes [1].
  • We find that in addition to insulin the insulinoma express the normal beta-cell markers Pdx-1, IAPP, and Glut-2, and that these markers are absent from the glucagonoma: a reflection of the normal alpha-cell [2].
  • Small interfering RNA (siRNA) directed against Pdx-1 specifically reduced the levels of Pdx-1 protein and Syt1 transcript in insulinoma lines [3].
  • The aim of the present study was to determine, in weanling Wistar rats, the effect of a maternal high-fat diet (HFD) during defined periods of gestation and lactation, on body weight, circulating glucose and insulin concentrations, and the expression of GLUT-2, GK and Pdx-1 [4].

High impact information on Pdx1

  • Here we describe the regulation of the expression of IDX-1, C/EBPbeta, and insulin at the mRNA and protein levels in pancreatic islets in animal models of diabetes mellitus [1].
  • Our findings indicate that the differential dysregulation of both IDX-1 and C/EBPbeta, in response to sustained hyperglycemia or hyperlipidemia, may be involved in the impairment of insulin gene expression during the manifestation of diabetes mellitus [1].
  • These islets contained small, highly condensed but clearly active B cells with prominent IPF1/STF1-positive nuclei, surrounded by densely packed glucagon-negative cells with reduced cytoplasm [5].
  • The pattern of expression, relative abundance and transcriptional regulatory activity suggests that IDX-1 may be involved in the regulation of islet hormone genes and in cellular differentiation in the endocrine pancreas and the duodenum [6].
  • In co-transfection experiments IDX-1 transactivates reporter constructs containing somatostatin promoter sequences, and mutation of the IDX-1 binding sites attenuates transactivation [6].

Chemical compound and disease context of Pdx1


Biological context of Pdx1

  • Pdx1 level defines pancreatic gene expression pattern and cell lineage differentiation [8].
  • 1. Pdx1 defines pancreatic cell lineage differentiation [8].
  • To define the transcription factor responsible for pancreatic cell differentiation, we employed the reverse tetracycline-dependent transactivator system in INS-I cell-derived subclones INSralphabeta and INSrbeta to achieve tightly controlled and conditional expression of wild type Pdx1 or its dominant-negative mutant, as well as brain-4 [8].
  • Pdx1, a homeodomain transcription factor required for pancreas development, maps to rat chromosome 12 [9].
  • Transfection of insulin-producing INS-1E cells and primary rat beta-cells with a constitutively active form of the Notch receptor down-regulated Pdx1 and insulin expression in INS-1E cells but not in primary beta-cells [10].

Anatomical context of Pdx1

  • Pdx1 has been shown to convert hepatocytes into both exocrine and endocrine pancreatic cells in mice, but it fails to selectively convert hepatocytes into pure insulin-producing cells (IPCs) [11].
  • AIM/HYPOTHESIS: Maturation of the beta cells in the islets of Langerhans is dependent upon sequential activation of different transcription factors such as Pdx-1 and Nkx6 [12].
  • Over-expression of Nkx6.1 or Pdx-1 in cell lines resulted in a significantly increased sensitivity to IL-1beta [12].
  • These cells were negative for endocrine markers but expressed Pdx1, a marker for pancreatic stem cells [13].
  • These results provide the evidence that immature intestinal epithelial cells can differentiate into multiple hormone-producing enteroendocrine cells in response to overexpression of Pdx1 [14].

Associations of Pdx1 with chemical compounds

  • Ipf1/Pdx1 gene transfer to isolated P. obesus islets normalized the defect in glucose-stimulated insulin gene expression and prevented the rapid depletion of insulin content after exposure to high glucose [15].
  • The palmitic acid effect on IDX-1 was correlated with decreases in GLUT2 and glucokinase expression of 40 and 25%, respectively, at both the mRNA and protein levels [16].
  • The decrease in insulin gene promoter activity was associated with reductions in the binding activities of both STF-1 and C1 activator, and these were partially reversed by lowering the glucose concentration [17].
  • It was established that activities of NAD(P)H reductase and content of cytochrome P450 were normalised in liver microsomes of hyperlipidemic rats, if the animals were treated with STF1 (2 g/bwkg for 9 days in drinking water parallel with fat-rich diet feeding) [18].

Physical interactions of Pdx1

  • Here we show that exposure of isolated rat pancreatic islets to palmitic acid induced a approximately 70% decrease in IDX-1 mRNA and protein expression as well as 40 and 65% decreases in the binding activity of IDX-1 for its cognate cis-regulatory elements of the Glut2 and insulin promoters, respectively [16].

Regulatory relationships of Pdx1

  • We observed that Kir6.2 protein was expressed de novo in IEC-6 cells expressing both Pdx-1 and Isl-1 but not in cells expressing Pdx-1 alone [19].

Other interactions of Pdx1

  • RNAi-mediated suppression of Nkx6.1 expression in class 3 cells also caused a decrease in GSIS from 13.9- to 3.7-fold, whereas suppression of Pdx1 reduced absolute amounts of insulin secretion without affecting fold response [20].
  • Induction of dominant-negative Pdx1 in INSralphabeta cells resulted in differentiation of insulin-producing beta-cells into glucagon-containing alpha-cells without altering brain4 expression [8].
  • The absence of Pdx1 and the expression of brain-4 distinguish alpha-cells from other pancreatic endocrine cell lineages [8].
  • Cytokine-induced NF-kappa B activation decreased Pdx-1 and increased c-Myc expression [21].
  • 2. To investigate the regulation of Kir6.2 gene expression, we assessed Kir6.2 expression in IEC-6 cells expressing Pdx-1 and/or Isl-1 [19].

Analytical, diagnostic and therapeutic context of Pdx1


  1. Differential expression of the insulin gene transcriptional repressor CCAAT/enhancer-binding protein beta and transactivator islet duodenum homeobox-1 in rat pancreatic beta cells during the development of diabetes mellitus. Seufert, J., Weir, G.C., Habener, J.F. J. Clin. Invest. (1998) [Pubmed]
  2. mRNA profiling of rat islet tumors reveals nkx 6.1 as a beta-cell-specific homeodomain transcription factor. Jensen, J., Serup, P., Karlsen, C., Nielsen, T.F., Madsen, O.D. J. Biol. Chem. (1996) [Pubmed]
  3. Pdx-1 enables insulin secretion by regulating synaptotagmin 1 gene expression. Nakajima-Nagata, N., Sugai, M., Sakurai, T., Miyazaki, J., Tabata, Y., Shimizu, A. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  4. Hyperglycaemia and reduced glucokinase expression in weanling offspring from dams maintained on a high-fat diet. Cerf, M.E., Muller, C.J., Du Toit, D.F., Louw, J., Wolfe-Coote, S.A. Br. J. Nutr. (2006) [Pubmed]
  5. Potent inhibitory effects of transplantable rat glucagonomas and insulinomas on the respective endogenous islet cells are associated with pancreatic apoptosis. Blume, N., Skouv, J., Larsson, L.I., Holst, J.J., Madsen, O.D. J. Clin. Invest. (1995) [Pubmed]
  6. IDX-1: a new homeodomain transcription factor expressed in rat pancreatic islets and duodenum that transactivates the somatostatin gene. Miller, C.P., McGehee, R.E., Habener, J.F. EMBO J. (1994) [Pubmed]
  7. Hedgehog signaling regulation of homeodomain protein islet duodenum homeobox-1 expression in pancreatic beta-cells. Thomas, M.K., Lee, J.H., Rastalsky, N., Habener, J.F. Endocrinology (2001) [Pubmed]
  8. Pdx1 level defines pancreatic gene expression pattern and cell lineage differentiation. Wang, H., Maechler, P., Ritz-Laser, B., Hagenfeldt, K.A., Ishihara, H., Philippe, J., Wollheim, C.B. J. Biol. Chem. (2001) [Pubmed]
  9. Pdx1, a homeodomain transcription factor required for pancreas development, maps to rat chromosome 12. Yokoi, N., Serikawa, T., Walther, R. Exp. Anim. (1997) [Pubmed]
  10. Notch signaling: a mediator of beta-cell de-differentiation in diabetes? Darville, M.I., Eizirik, D.L. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  11. High glucose is necessary for complete maturation of Pdx1-VP16-expressing hepatic cells into functional insulin-producing cells. Cao, L.Z., Tang, D.Q., Horb, M.E., Li, S.W., Yang, L.J. Diabetes (2004) [Pubmed]
  12. Gene expression profiles during beta cell maturation and after IL-1beta exposure reveal important roles of Pdx-1 and Nkx6.1 for IL-1beta sensitivity. Nielsen, K., Kruhøffer, M., Orntoft, T., Sparre, T., Wang, H., Wollheim, C., Jørgensen, M.C., Nerup, J., Karlsen, A.E. Diabetologia (2004) [Pubmed]
  13. Label-retaining cells in the rat pancreas: location and differentiation potential in vitro. Duvillié, B., Attali, M., Aiello, V., Quemeneur, E., Scharfmann, R. Diabetes (2003) [Pubmed]
  14. Differentiation of immature enterocytes into enteroendocrine cells by Pdx1 overexpression. Yamada, S., Kojima, H., Fujimiya, M., Nakamura, T., Kashiwagi, A., Kikkawa, R. Am. J. Physiol. Gastrointest. Liver Physiol. (2001) [Pubmed]
  15. IPF1/PDX1 deficiency and beta-cell dysfunction in Psammomys obesus, an animal With type 2 diabetes. Leibowitz, G., Ferber, S., Apelqvist A, n.u.l.l., Edlund, H., Gross, D.J., Cerasi, E., Melloul, D., Kaiser, N. Diabetes (2001) [Pubmed]
  16. Fatty acids decrease IDX-1 expression in rat pancreatic islets and reduce GLUT2, glucokinase, insulin, and somatostatin levels. Gremlich, S., Bonny, C., Waeber, G., Thorens, B. J. Biol. Chem. (1997) [Pubmed]
  17. Glucose rapidly and reversibly decreases INS-1 cell insulin gene transcription via decrements in STF-1 and C1 activator transcription factor activity. Olson, L.K., Qian, J., Poitout, V. Mol. Endocrinol. (1998) [Pubmed]
  18. Membrane stabilising effects of natural polyphenols and flavonoids from Sempervivum tectorum on hepatic microsomal mixed-function oxidase system in hyperlipidemic rats. Blázovics, A., Lugasi, A., Kemény, T., Hagymási, K., Kéry, A. Journal of ethnopharmacology. (2000) [Pubmed]
  19. Regulation of ATP-sensitive potassium channel subunit Kir6.2 expression in rat intestinal insulin-producing progenitor cells. Hashimoto, T., Nakamura, T., Maegawa, H., Nishio, Y., Egawa, K., Kashiwagi, A. J. Biol. Chem. (2005) [Pubmed]
  20. The Nkx6.1 homeodomain transcription factor suppresses glucagon expression and regulates glucose-stimulated insulin secretion in islet beta cells. Schisler, J.C., Jensen, P.B., Taylor, D.G., Becker, T.C., Knop, F.K., Takekawa, S., German, M., Weir, G.C., Lu, D., Mirmira, R.G., Newgard, C.B. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  21. A comprehensive analysis of cytokine-induced and nuclear factor-kappa B-dependent genes in primary rat pancreatic beta-cells. Cardozo, A.K., Heimberg, H., Heremans, Y., Leeman, R., Kutlu, B., Kruhøffer, M., Ørntoft, T., Eizirik, D.L. J. Biol. Chem. (2001) [Pubmed]
  22. Silymarin induces recovery of pancreatic function after alloxan damage in rats. Soto, C., Mena, R., Luna, J., Cerbón, M., Larrieta, E., Vital, P., Uría, E., Sánchez, M., Recoba, R., Barrón, H., Favari, L., Lara, A. Life Sci. (2004) [Pubmed]
  23. Expression of stem cell markers and transcription factors during the remodeling of the rat pancreas after duct ligation. Peters, K., Panienka, R., Li, J., Klöppel, G., Wang, R. Virchows Arch. (2005) [Pubmed]
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