Increased insulin sensitivity and hypoglycaemia in mice lacking the p85α subunit of phosphoinositide 3–kinase (original) (raw)

• Letter
• Published: February 1999
• Youki Tsuji1,
• Shinobu Satoh5,
• Hideaki Minoura1,
• Koji Murakami1,
• Akira Okuno1,
• Kouichi Inukai1,
• Tomoichiro Asano1,
• Yasushi Kaburagi1,
• Kohjiro Ueki1,
• Hiromu Nakajima6,
• Toshiaki Hanafusa6,
• Yuji Matsuzawa6,
• Hisahiko Sekihara5,
• Yuxin Yin7,
• J. Carl Barrett7,
• Hideaki Oda2,
• Takatoshi Ishikawa2,
• Yasuo Akanuma8,
• Issei Komuro1,
• Misao Suzuki9,
• Ken-ichi Yamamura10,
• Tatsuhiko Kodama3,
• Harumi Suzuki12,
• Shigeo Koyasu12,
• Shinichi Aizawa11,
• Kazuyuki Tobe1,
• Yasuhisa Fukui4,
• Yoshio Yazaki1 &
• …
• Takashi Kadowaki1

Nature Genetics volume 21, pages 230–235 (1999)Cite this article

Abstract

The hallmark of type 2 diabetes, the most common metabolic disorder, is a defect in insulin–stimulated glucose transport in peripheral tissues. Although a role for phosphoinositide–3–kinase (PI3K) activity in insulin–stimulated glucose transport and glucose transporter isoform 4 (Glut4) translocation has been suggested in vitro1,2, its role in vivo and the molecular link between activation of PI3K and translocation has not yet been elucidated. To determine the role of PI3K in glucose homeostasis, we generated mice with a targeted disruption of the gene encoding the p85α regulatory subunit of PI3K (Pik3r1; refs 3, 4, 5). Pik3r1 −/− mice showed increased insulin sensitivity and hypoglycaemia due to increased glucose transport in skeletal muscle and adipocytes. Insulin–stimulated PI3K activity associated with insulin receptor substrates (IRSs) was mediated via full–length p85α in wild–type mice, but via the p50α alternative splicing isoform of the same gene6,7 in Pik3r1 −/− mice. This isoform switch was associated with an increase in insulin–induced generation of phosphatidylinositol(3,4,5)triphosphate (PtdIns(3,4,5)P3) in Pik3r1 −/− adipocytes and facilitation of Glut4 translocation from the low–density microsome (LDM) fraction to the plasma membrane (PM). This mechanism seems to be responsible for the phenotype of Pik3r1 −/− mice, namely increased glucose transport and hypoglycaemia. Our work provides the first direct evidence that PI3K and its regulatory subunit have a role in glucose homeostasis in vivo.

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Acknowledgements

We thank T. Katada, O. Hazeki, B.B. Kahn and E.U. Frevert for helpful discussion; N. Takeda for microinjection of ES cells; and S.W. Cushman for anti–Glut4 antibody. This work was supported by a Grant–in–Aid for Creative Basic Research (10NP0201) from the Ministry of Education, Science, Sports, and Culture of Japan, and by a grant from Uehara Memorial Foundation (T.K.).

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Authors and Affiliations

1. Department of Internal Medicine, University of Tokyo, Tokyo, 113–8655, Japan
   Yasuo Terauchi, Youki Tsuji, Hideaki Minoura, Koji Murakami, Akira Okuno, Kouichi Inukai, Tomoichiro Asano, Yasushi Kaburagi, Kohjiro Ueki, Issei Komuro, Kazuyuki Tobe, Yoshio Yazaki & Takashi Kadowaki
2. Department of Pathology, University of Tokyo, Tokyo, 113–8655, Japan
   Hideaki Oda & Takatoshi Ishikawa
3. Department of Molecular Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, 113–8655, Japan
   Tatsuhiko Kodama
4. Department of Applied Biological Chemistry, Laboratory of Biological Chemistry, University of Tokyo, Tokyo, 113–8655 , Japan
   Yasuhisa Fukui
5. Third Department of Internal Medicine, Yokohama City University, Yokohama, 236, Japan
   Shinobu Satoh & Hisahiko Sekihara
6. Second Department of Internal Medicine, Osaka University, Osaka, 565, Japan
   Hiromu Nakajima, Toshiaki Hanafusa & Yuji Matsuzawa
7. Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, 27709, North Carolina, USA
   Yuxin Yin & J. Carl Barrett
8. Institute for Diabetes Care and Research, Asahi Life Foundation, Tokyo, 100, Japan
   Yasuo Akanuma
9. Laboratory of Transgenic Technology, Kumamoto University School of Medicine, Kumamoto, 860, Japan
   Misao Suzuki
10. Department of Developmental Genetics, Kumamoto University School of Medicine, Kumamoto, 860, Japan
    Ken-ichi Yamamura
11. Department of Morphogenesis, Institute of Molecular Embryology and Genetics, Kumamoto University School of Medicine, Kumamoto, 860, Japan
    Shinichi Aizawa
12. Department of Immunology, Keio University School of Medicine, Tokyo, 160, Japan
    Harumi Suzuki & Shigeo Koyasu

Authors

1. Yasuo Terauchi
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2. Youki Tsuji
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3. Shinobu Satoh
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4. Hideaki Minoura
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5. Koji Murakami
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6. Akira Okuno
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7. Kouichi Inukai
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8. Tomoichiro Asano
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9. Yasushi Kaburagi
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10. Kohjiro Ueki
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11. Hiromu Nakajima
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12. Toshiaki Hanafusa
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13. Yuji Matsuzawa
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14. Hisahiko Sekihara
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15. Yuxin Yin
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16. J. Carl Barrett
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17. Hideaki Oda
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18. Takatoshi Ishikawa
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19. Yasuo Akanuma
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20. Issei Komuro
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21. Misao Suzuki
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22. Ken-ichi Yamamura
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23. Tatsuhiko Kodama
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24. Harumi Suzuki
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25. Shigeo Koyasu
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26. Shinichi Aizawa
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27. Kazuyuki Tobe
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28. Yasuhisa Fukui
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29. Yoshio Yazaki
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30. Takashi Kadowaki
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Correspondence toTakashi Kadowaki.

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Terauchi, Y., Tsuji, Y., Satoh, S. et al. Increased insulin sensitivity and hypoglycaemia in mice lacking the p85α subunit of phosphoinositide 3–kinase.Nat Genet 21, 230–235 (1999). https://doi.org/10.1038/6023

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• Received: 11 August 1998
• Accepted: 29 December 1998
• Issue Date: February 1999
• DOI: https://doi.org/10.1038/6023

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