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.
Address correspondence and reprint requests to Stéphane Schurmans, IRIBHM-IBMM-ULB, rue des Professeurs Jeener et Brachet 12, 6041 Gosselies, Belgium. E-mail:.
Received for publication 5 March 2002 and accepted in revised form 8 May 2002. Posted on the World Wide Web at http://www.diabetes.org/diabetes/rapidpubs.shtml on 7 June 2002.
ARE, adenylate/uridylate-rich element; HA, hemagglutinin A; MAP, mitogen-activated protein; PKB, protein kinase B; QTL, quantitative trait locus; SH, Src homology; SV40, simian virus 40; UTR, untranslated region.