Increased insulin sensitivity and hypoglycaemia in mice lacking the P85 alpha subunit of phosphoinositide 3-kinase

The hallmark of type 2 diabetes, the most common metabolic disorder, is a d efect in insulin-stimulated glucose transport in peripheral tissues. Althou gh a role for phosphoinositide-3-kinase (PI3K) activity in insulin-stimulat ed glucose transport and glucose transporter isoform 4 (Glut4) translocatio n has been suggested in vitro(1,2), its role in vive and the molecular link between activation of PI3K and translocation has not yet been elucidated. To determine the role of PI3K in glucose homeostasis, we generated mice wit h a targeted disruption of the gene encoding the p85 alpha regulatory subun it of PI3K (Pik3r1; refs 3-5). Pik3r1(-/-) mice showed increased insulin se nsitivity and hypoglycaemia due to increased glucose transport in skeletal muscle and adipocytes. Insulin-stimulated PI3K activity associated with ins ulin receptor substrates (IRSs) was mediated via full-length p85 alpha in w ild-type mice, but via the p50 alpha alternative splicing isoform of the sa me gene(6,7) in Pik3r1(-/-) mice. This isoform switch was associated with a n increase in insulin-induced generation of phosphatidylinositol(3, 4, 5)tr iphosphate (PtdIns(3, 4, 5)P-3) in Pik3r1(-/-) adipocytes and facilitation of Glut4 translocation from the law-density microsome (LDM) fraction to the plasma membrane (PM). This mechanism seems to be responsible for the pheno type of Pik3r1(-/-) mice, namely increased glucose transport and hypoglycae mia. Our work provides the first direct evidence that PI3K and its regulato ry subunit have a role in glucose homeostasis in vive.