[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 [GB]
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