The Gene INPPL 1 , Encoding the Lipid Phosphatase SHIP 2 , Is a Candidate for Type 2 Diabetes In Rat and Man

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. Diabetes 51:2012–2017, 2002 Recent data from knock-out mice (1) and in vitro studies (2–5) have identified type II SH2domain–containing inositol 5-phosphatase, or “SHIP2,” as a critical and essential negative regulator of insulin signaling and sensitivity. Indeed, decreased expression of SHIP2 and SHIP2 deficiency in mice leads to increased insulin sensitivity, whereas SHIP2 overexpression in various insulin-sensitive cell lines leads to decreased insulin signaling, i.e., insulin resistance. Given the importance of SHIP2 in the control of insulin sensitivity, we postulated that mutation(s) positively affecting SHIP2 activity, function, and/or expression might contribute to insulin resistance, a hallmark of type 2 diabetes.