The lipid phosphatase SHIP2 controls insulin sensitivity

Insulin is the primary hormone involved in glucose homeostasis, and impairm ent of insulin action and/or secretion has a critical role in the pathogene sis of diabetes mellitus. Type-II SH2-domain-containing inositol 5-phosphat ase, or 'SHIP2', is a member of the inositol polyphosphate 5-phosphatase fa mily(1). In vitro studies have shown that SHIP2, in response to stimulation by numerous growth factors and insulin, is closely linked to signalling ev ents mediated by both phosphoinositide-3-OH kinase and Ras/mitogen-activate d protein kinase(2-5). Here we report the generation of mice lacking the SH IP2 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 a nd insulin sensitivity associated with an increased recruitment of the GLUT 4 glucose transporter and increased glycogen synthesis in skeletal muscles. Our results show that SHIP2 is a potent negative regulator of insulin sign alling and insulin sensitivity in vivo.