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Dominant-negative mutant hepatocyte nuclear factor 1α induces diabetes in transgenic-cloned pigs

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Abstract

Pigs have been recognized as an excellent biomedical model for investigating a variety of human health issues. We developed genetically modified pigs that exhibit the apparent symptoms of diabetes. Transgenic cloned pigs carrying a mutant human hepatocyte nuclear factor 1α gene, which is known to cause the type 3 form of maturity-onset diabetes of the young, were produced using a combined technology of intracytoplasmic sperm injection-mediated gene transfer and somatic cell nuclear transfer. Although most of the 22 cloned offspring obtained died before weaning, four pigs that lived for 20–196 days were diagnosed as diabetes mellitus with nonfasting blood glucose levels greater than 200 mg/dl. Oral glucose tolerance test on a cloned pig also revealed a significant increase of blood glucose level after glucose loading. Histochemical analysis of pancreas tissue from the cloned pigs showed small and irregularly formed Langerhans Islets, in which poor insulin secretion was detected.

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Acknowledgments

This work was supported by the Program for Promotion of Basic Research Activities for Innovative Bioscience (PROBRAIN), Tokyo, and Japan Science Technology Agency, ERATO, Nakauchi Stem Cell and Organ Regeneration Project, Tokyo. We thank K. Urakami for useful suggestion and R. Ohnishi and T. Okada for their technical assistance.

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Authors and Affiliations

  1. BIOS Research Laboratory Inc., 4-28 Amanuma, Hiratsuka, Kanagawa, 254-0031, Japan

    Kazuhiro Umeyama, Masahito Watanabe & Keizaburo Miki

  2. Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, 1-1-1 Higashimita, Tama, Kawasaki, Kanagawa, 214-8571, Japan

    Hitoshi Saito, Mayuko Kurome, Sadaaki Tohi, Hitomi Matsunari & Hiroshi Nagashima

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  1. Kazuhiro Umeyama
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  2. Masahito Watanabe
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  3. Hitoshi Saito
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  4. Mayuko Kurome
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  5. Sadaaki Tohi
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  6. Hitomi Matsunari
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  7. Keizaburo Miki
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  8. Hiroshi Nagashima
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Correspondence to Hiroshi Nagashima.

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Umeyama, K., Watanabe, M., Saito, H. et al. Dominant-negative mutant hepatocyte nuclear factor 1α induces diabetes in transgenic-cloned pigs. Transgenic Res 18, 697–706 (2009). https://doi.org/10.1007/s11248-009-9262-3

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  • DOI: https://doi.org/10.1007/s11248-009-9262-3

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