[en] Genetic susceptibility to type 2 diabetes involves many genes, most of which are still unknown. The lipid phosphatase SHIP2 is a potent negative regulator of insulin signaling and sensitivity in vivo and is thus a good candidate gene. Here we report the presence of SHIP2 gene mutations associated with type 2 diabetes in rats and humans. The R1142C mutation specifically identified in Goto-Kakizaki (GK) and spontaneously hypertensive rat strains disrupts a potential class II ligand for Src homology (SH)-3 domain and slightly impairs insulin signaling in cell culture. In humans, a deletion identified in the SHIP2 3' untranslated region (UTR) of type 2 diabetic subjects includes a motif implicated in the control of protein synthesis. In cell culture, the deletion results in reporter messenger RNA and protein overexpression. Finally, genotyping of a cohort of type 2 diabetic and control subjects showed a significant association between the deletion and type 2 diabetes. Altogether, our results show that mutations in the SHIP2 gene contribute to the genetic susceptibility to type 2 diabetes in rats and humans
The gene INPPL1, encoding the lipid phosphatase SHIP2, is a candidate for type 2 diabetes in rat and man
Publication date :
2002
Journal title :
Diabetes
ISSN :
0012-1797
eISSN :
1939-327X
Publisher :
American Diabetes Association, Alexandria, United States - Virginia
Volume :
51
Pages :
2012-2017
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
Fonds de la Recherche Scientifique Médicale de Belgique, Interreg II (cofinanced by the Région Wallonne and the European Commission, FEDER), Banque Nationale de Belgique, Action de Recherche Concertée, and a grant from The Free University of Brussels Wellcome Trust
Clement S., Krause U., Desmedt F., Tanti J.F., Behrends J., Pesesse X., Sasaki T., Penninger J., Doherty M., Malaisse W., Dumont J.E., Le Marchand-Brustel Y., Erneux C., Hue L., Schurmans S. (2001) The lipid phosphatase SHIP2 controls insulin sensitivity. Nature 409:92-97.
Ishihara H., Sasaoka T., Hori H., Wada T., Hirai H., Haruta T., Langlois W.J., Kobayashi M. (1999) 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.
Sasaoka T., Hori H., Wada T., Ishiki M., Haruta T., Ishihara H., Kobayashi M. (2001) SH2-containing inositol phosphatase 2 negatively regulates insulin-induced glycogen synthesis in L6 myotubes. Diabetologia 44:1258-1267.
Wada T., Sasaoka T., Funaki M., Hori H., Murakami S., Ishiki M., Haruta T., Asano T., Ogawa W., Ishihara H., Kobayashi M. (2001) Overexpression of SH2-containing inositol phosphatase 2 results in negative regulation of insulin-induced metabolic actions in 3T3-L1 adipocytes via its 5′-phosphatase catalytic activity. Mol Cell Biol 21:1633-1646.
Blero D., De Smedt F., Pesesse X., Paternotte N., Moreau C., Payrastre B., Erneux C. (2001) The SH2 domain containing inositol 5-phosphatase SHIP2 controls phosphatidylinositol 3,4,5-trisphosphate levels in CHO-IR cells stimulated by insulin. Biochem Biophys Res Commun 282:839-843.
Szpirer C., Van Vooren P., Rivière M., Scohy S., Collau G., Szpirer J. (2000) Localization of 54 rat genes, and definition of new synteny groups conserved in the human and the rat. Mamm Genome 11:729-735.
Galli J., Li L.H., Glaser A., Östenson C.G., Jiao H., Fakhrai-Rad H., Jacob H.J., Lander E.S., Luthman H. (1996) Genetic analysis of non-insulin dependent diabetes mellitus in the GK rat. Nat Genet 12:31-37.
Gauguier D., Froguel P., Parent V., Bernard C., Bihoreau M.T., Portha B., James M.R., Penicaud L., Lathrop M., Ktorza A. (1996) Chromosomal mapping of genetic loci associated with non-insulin dependent diabetes in the GK rat. Nature Genetics 12:38-43.
Aitman T.J., Gotoda T., Evans A.L., Imrie H., Heath K.E., Trembling P.M., Truman H., Wallace C.A., Rahman A., Doré C., Flint J., Kren V., Zidek V., Kurtz T.W., Pravanec M., Scott J. (1997) Quantitative trait loci for cellular defects in glucose and fatty acid metabolism in hypertensive rats. Nat Genet 16:197-201.
Kay B.K., Williamson M.P., Sudol M. (2000) The importance of being a proline: The interaction of proline-rich motifs in signalling proteins with their cognate domains. FASEB J 14:231-241.
Feng S., Chen J.K., Yu H., Simon J.A., Schreiber S.L. (1994) Two binding orientations for peptides to the Src SH3 domain: Development of a general model for SH3-ligand interactions. Science 266:1241-1247.
Aman M.J., Walk S.F., March M.E., Su H.P., Carver D.J., Ravichandran K.S. (2000) Essential role for the C-terminal noncatalytic region of SHIP in FcgammaRIIB1-mediated inhibitory signaling. Mol Cell Biol 20:3576-3589.
Damen J.E., Ware M.D., Kaleshnikoff J., Hugues M.R., Krystal G. (2001) SHIP's C-terminus is essential for its hydrolysis of PIP(3) and inhibition of mast cell degranulation. Blood 97:1343-1351.
Chen C.A., Shyu A.B. (1995) AU-rich elements: Characterization and importance in mRNA degradation. Trends Biochem Sci 20:465-470.
Bakheet T., Frevel M., Williams B.R.G., Greer W., Khabar K.S.A. (2001) ARED: Human AU-rich element-containing mRNA database reveals an unexpectedly diverse functional repertoire of encoded proteins. Nucl Acids Res 29:246-254.
