Insulin is the primary hormone involved in glucose homeostasis, and impairment of insulin action and/or secretion has a critical role in the pathogenesis of diabetes mellitus. Type-II SH2-domain-containing inositol 5-phosphatase, or ‘SHIP2’, is a member of the inositol polyphosphate 5-phosphatase family1. In vitro studies have shown that SHIP2, in response to stimulation by numerous growth factors and insulin, is closely linked to signalling events mediated by both phosphoinositide-3-OH kinase and Ras/mitogen-activated protein kinase2,3,4,5. Here we report the generation of mice lacking the SHIP2 gene. Loss of SHIP2 leads to increased sensitivity to insulin, which is characterized by severe neonatal hypoglycaemia, deregulated expression of the genes involved in gluconeogenesis, and perinatal death. Adult mice that are heterozygous for the SHIP2 mutation have increased glucose tolerance and insulin sensitivity associated with an increased recruitment of the GLUT4 glucose transporter and increased glycogen synthesis in skeletal muscles. Our results show that SHIP2 is a potent negative regulator of insulin signalling and insulin sensitivity in vivo.
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We thank B. Payrastre, G. Giuriato, and J. and R. Merino for sharing unpublished results; E. Marion, T. Grémeaux and L. Maisin for technical assistance; A. Nagy for the R1 ES cells; P. Johnson for rat C/EBPβ cDNA clone; and G. Schütz for mouse TAT-5′, G-6-Pase, C/EBPα and aldolase B cDNA clones. This work and U.K. were supported by the Belgian Programme on Interuniversity Poles of Attraction initiated by the Belgian State, Prime Minister's Office, Federal Service for Science, Technology and Culture, the Fonds de la Recherche Scientifique Médicale de Belgique, Biomed 2 program, Association contre le Cancer, and Télévie. S.C. is a fellow of the FRIA; F.D. and S.S. are Chargé de Recherche and Chercheur Qualifié of the Belgian FNRS, respectively. J.B. was supported by the Deutsche Forschungsgemeinschaft. Y.L.M.B. and J.F.T. are supported by Institut National de la Santé et de la Recherche Médicale (France).
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Clément, S., Krause, U., Desmedt, F. et al. The lipid phosphatase SHIP2 controls insulin sensitivity. Nature 409, 92–97 (2001). https://doi.org/10.1038/35051094
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