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Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia

Nature Medicine volume 6, pages 568–572 (2000)Cite this article

Abstract

Insulin gene expression is restricted to islet β cells of the mammalian pancreas through specific control mechanisms mediated in part by specific transcription factors1,2. The protein encoded by the pancreatic and duodenal homeobox gene 1 (PDX-1) is central in regulating pancreatic development and islet cell function3. PDX-1 regulates insulin gene expression and is involved in islet cell-specific expression of various genes4,5,6,7. Involvement of PDX-1 in islet-cell differentiation and function has been demonstrated mainly by ‘loss-of-function’ studies8,9,10,11. We used a ‘gain-of-function’ approach to test whether PDX-1 could endow a non-islet tissue with pancreatic β-cell characteristics in vivo. Recombinant-adenovirus-mediated gene transfer of PDX-1 to the livers of BALB/C and C57BL/6 mice activated expression of the endogenous, otherwise silent, genes for mouse insulin 1 and 2 and prohormone convertase 1/3 (PC 1/3). Expression of PDX-1 resulted in a substantial increase in hepatic immunoreactive insulin content and an increase of 300% in plasma immunoreactive insulin levels, compared with that in mice treated with control adenovirus. Hepatic immunoreactive insulin induced by PDX-1 was processed to mature mouse insulin 1 and 2 and was biologically active; it ameliorated hyperglycemia in diabetic mice treated with streptozotocin. These data indicate the capacity of PDX-1 to reprogram extrapancreatic tissue towards a β-cell phenotype, may provide a valuable approach for generating ‘self’ surrogate β cells, suitable for replacing impaired islet-cell function in diabetics.

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Figure 1: RT–PCR analysis of mRNA for mI-1, mI-2, human insulin, PDX-1 and β-actin.
Figure 2: Immunohistochemical staining of livers.
Figure 3: Liver from PDX-1 treated mice contain processed insulin and express the prohormone convertase PC1/3.
Figure 4: Ectopic expression of PDX-1 in mice livers ameliorates streptozotocin-induced hyperglycemia.

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Acknowledgements

We thank C. Gal, Y. Cohen, Y. Ariav, P. Keren, A. Shaish, M. Tal and D. Castel for technical support; M.D. Walker and C.B. Newgard for critically reviewing the manuscript; R. Skutelsky and H. Halkin for editing the manuscript; and B. Goldman for support. The study was partially supported by a grant from Israel Ministry of Health-Mendel Chodowski-Fund.

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Authors and Affiliations

  1. Endocrine Institute, Sheba Medical Center, Tel-Hashomer, 52621, Israel

    Sarah Ferber, Hofit Cohen, Idit Ber, Rhona Seijffers & Avraham Karasik

  2. Deptartment of Cardiology Sourasky Medical Center, Tel-Aviv, 64239, Israel

    Amir Halkin

  3. Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv, 69978, Israel

    Idit Ber, Rhona Seijffers, Juri Kopolovic & Avraham Karasik

  4. Life Science Dep. Tel-Aviv University, Ramat-Aviv, 69978, Israel

    Yulia Einav

  5. Pathology Institute, Sheba Medical Center, Tel-Hashomer, 52621, Israel

    Iris Goldberg, Iris Barshack & Juri Kopolovic

  6. Department of Endocrinology and Metabolism, The Hebrew University-Hadassah Medical Center, Jerusalem, 91120 , Israel

    Nurit Kaiser

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  1. Sarah Ferber
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Correspondence to Sarah Ferber.

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Ferber, S., Halkin, A., Cohen, H. et al. Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia. Nat Med 6, 568–572 (2000). https://doi.org/10.1038/75050

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