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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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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DOI: https://doi.org/10.1038/6023
