The lipid phosphatase SHIP2 controls insulin sensitivity

A Corrigendum to this article was published on 14 October 2004

Abstract

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Targeted disruption of SHIP2 gene.
Figure 2: Impaired glucose homeostasis in SHIP2-/- newborns.
Figure 3: Increased insulin sensitivity in adult SHIP2+/- mice.

References

  1. 1

    Pesesse, X., Deleu, S., De Smedt, F., Drayer, L. & Erneux, C. Identification of a second SH2-domain-containing protein closely related to the phosphatidylinositol polyphosphate 5-phosphatase SHIP. Biochem. Biophys. Res. Commun. 239, 697 –700 (1997).

    CAS  Article  Google Scholar 

  2. 2

    Habib, T., Hejna, J. A., Moses, R. E. & Decker, S. J. Growth factors and insulin stimulate tyrosine phosphorylation of the 51C/SHIP2 protein. J. Biol. Chem. 273, 18605– 18609 (1998).

    CAS  Article  Google Scholar 

  3. 3

    Pesesse, X. et al. The SH2 domain containing inositol 5-phosphatase SHIP2 displays phosphatidylinositol 3,4,5-triphosphate and inositol 1,3,4,5-tetrakisphosphate 5-phosphatase activity. FEBS Lett. 437, 301–303 (1998).

    CAS  Article  Google Scholar 

  4. 4

    Wisniewski, D. et al. A novel SH2-containing phosphatidylinositol 3,4,5-triphosphate 5-phosphatase (SHIP2) is constitutively tyrosine phosphorylated and associated with src homologous and collagen gene (SHC) in chronic myelogenous leukemia progenitor cells. Blood 93, 2707– 2720 (1999).

    CAS  Article  Google Scholar 

  5. 5

    Ishihara, H. et al. Molecular cloning of rat SH2-containing inositol phosphatase 2 (SHIP2) and its role in the regulation of insulin signaling. Biochem. Biophys. Res. Commun. 260, 265– 272 (1999).

    CAS  Article  Google Scholar 

  6. 6

    Schurmans, S. et al. The mouse SHIP2 (Inppl1) gene: complementary DNA, genomic structure, promoter analysis, and gene expression in the embryo and adult mouse. Genomics 62, 260– 271 (1999).

    CAS  Article  Google Scholar 

  7. 7

    Liu, Q. et al. The SH2-containing inositol polyphosphate 5-phosphatase, SHIP, is expressed during hematopoiesis and spermatogenesis. Blood 91, 2753–2759 (1998).

    CAS  Article  Google Scholar 

  8. 8

    Lteif, A. N. & Schwenk, W. F. Hypoglycemia in infants and children. Endocrinol. Metab. Clin. North Am. 28, 619–646 (1999).

    CAS  Article  Google Scholar 

  9. 9

    Girard, J., Ferré, P., Pégorier, J.-P. & Duée, P.-H. Adaptations of glucose and fatty acid metabolism during perinatal period and suckling-weaning transition. Physiol. Rev. 72, 507–562 (1992).

    CAS  Article  Google Scholar 

  10. 10

    Girard, J. & Pégorier, J.-P. An overview of early post-partum nutrition and metabolism. Biochem. Soc. Trans. 26, 69–74 (1998).

    CAS  Article  Google Scholar 

  11. 11

    Jones, C. T. (ed) The Development of the Metabolism in the Fetal Liver (Elsevier Biomedical Press, Elsevier, 1982).

    Google Scholar 

  12. 12

    Girard, J., Caquet, D., Bal, D. & Guillet, I. Control of rat liver phosphorylase, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase activities by insulin and glucagon during the perinatal period. Enzyme 15, 272–285 ( 1973).

    CAS  PubMed  Google Scholar 

  13. 13

    Yeung, D. & Oliver, I. T. Factors affecting the premature induction of phosphoenolpyruvate carboxykinase in neonatal rat liver. Biochem. J. 108, 325–331 (1968).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Hanson, R. W., Fisher, L., Ballard, F. J. & Reshef, L. The regulation of phosphoenolpyruvate carboxykinase in fetal rat liver. Enzyme 15, 97–100 ( 1973).

    CAS  PubMed  Google Scholar 

  15. 15

    Benvenisty, N. et al. in Lessons from Animal Diabetes (eds Shafrir, E. A. & Renold, A. E.) 717–733 (Libbey, London, 1984).

    Google Scholar 

  16. 16

    Czech, M. & Corvera, S. Signaling mechanisms that regulate glucose transport. J. Biol. Chem. 274, 1865 –1868 (1999).

    CAS  Article  Google Scholar 

  17. 17

    Nave, B. T. et al. Compartment-specific regulation of phosphoinositide 3-kinase by platelet-derived growth factor and insulin in 3T3-L1 adipocytes. Biochem. J. 318, 55–60 ( 1996).

    CAS  Article  Google Scholar 

  18. 18

    Corvera, S. & Czech, M. P. Direct targets of phosphoinositide 3-kinase products in membrane traffic and signal transduction. Trends Cell Biol. 8, 442–446 (1998).

    CAS  Article  Google Scholar 

  19. 19

    Warram, J. H., Rich, S. S. & Krolewski, A. S. in Joslin's Diabetes Mellitus (eds Kahn, C. R. & Weir, G. C.) 201–216 (Lea and Febiger, Philadelphia, 1995).

    Google Scholar 

  20. 20

    Kahn, B. Type 2 diabetes: when insulin secretion fails to compensate for insulin resistance. Cell 92, 593–596 (1998).

    CAS  Article  Google Scholar 

  21. 21

    Lee, Y.-H., Sauer, B., Johnson, P. F. & Gonzalez, F. J. Disruption of the C/EBPα gene in adult mouse liver. Mol. Cell. Biol. 17, 6014–6022 (1997).

    CAS  Article  Google Scholar 

  22. 22

    Bruyns, C., Pesesse, X., Moreau, C., Blero, D. & Erneux, C. The two SH2-domain-containing inositol 5-phosphatases SHIP1 and SHIP2 are coexpressed in human T lymphocytes. Biol. Chem. 380, 969–974 ( 1999).

    CAS  Article  Google Scholar 

  23. 23

    Simpson, I. A. et al. Insulin-stimulated translocation of glucose transporters in the isolated rat adipose cells. Biochim. Biophys. Acta 763, 393–407 (1983).

    CAS  Article  Google Scholar 

  24. 24

    Higaki, Y. et al. Insulin receptor substrate-2 is not necessary for insulin- and exercice-stimulated glucose transport in skeletal muscle. J. Biol. Chem. 274, 20791–20795 (1999).

    CAS  Article  Google Scholar 

  25. 25

    Stenbit, A. E. et al. Diverse effects of Glut 4 ablation on glucose uptake and glycogen synthesis in red and white skeletal muscle. J. Clin. Invest. 98, 629–634 (1996).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

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).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Stéphane Schurmans.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing