Increased insulin sensitivity and hypoglycaemia in mice lacking the p85α subunit of phosphoinositide 3–kinase

Abstract

The hallmark of type 2 diabetes, the most common metabolic disorder, is a defect in insulin-stimulated glucose transport in peripheral tissues. Although a role for phosphoinositide-3-kinase (PI3K) activity in insulin-stimulated glucose transport and glucose transporter isoform 4 (Glut4) translocation has been suggested in vitro, its role in vivo 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 with a targeted disruption of the gene encoding the p85alpha regulatory subunit of PI3K (Pik3r1; refs 3-5). Pik3r1-/- mice showed increased insulin sensitivity and hypoglycaemia due to increased glucose transport in skeletal muscle and adipocytes. Insulin-stimulated PI3K activity associated with insulin receptor substrates (IRSs) was mediated via full-length p85 alpha in wild-type mice, but via the p50 alpha alternative splicing isoform of the same gene in Pik3r1-/- mice. This isoform switch was associated with an increase in insulin-induced generation of phosphatidylinositol(3,4,5)triphosphate (PtdIns(3,4,5)P3) in Pik3r1-/- adipocytes and facilitation of Glut4 translocation from the low-density microsome (LDM) fraction to the plasma membrane (PM). This mechanism seems to be responsible for the phenotype of Pik3r1-/- mice, namely increased glucose transport and hypoglycaemia. Our work provides the first direct evidence that PI3K and its regulatory subunit have a role in glucose homeostasis in vivo.

Class IA phosphatidylinositol 3-kinase regulates osteoclastic bone resorption through protein kinase B–mediated vesicle transport

“…(40) Mice lacking only p85a are viable, (41) but mice lacking p85a, p55a, and p50a die immediately after birth, (34) indicating that p55a and p50a can compensate for the loss of p85a in vivo. In addition, PI3K activity is enhanced in mice lacking only p85a compared with wild-type mice, possibly because of higher p50a/p55a expression.…”

“…In addition, PI3K activity is enhanced in mice lacking only p85a compared with wild-type mice, possibly because of higher p50a/p55a expression. (41) A recent report by Munugalavadla and colleagues (42) described a bone phenotype in mice lacking only p85a, but as mentioned above, this strain is not a model of PI3K loss-of-function, and therefore does not provide information on the role of class IA PI3K in osteoclasts.…”

Nutritional upregulation of p85α expression is an early molecular manifestation of insulin resistance

“…the amounts of free p85 monomer and the p85-p110 heterodimer of the PI 3-kinase [9,[11][12][13][14]. PI 3-kinase belongs to the class 1a 3-kinases [10], which exist as heterodimers, and consists of a regulatory subunit (p85) that is tightly associated with a catalytic subunit, p110.…”

“…Subsequently, animals with a targeted disruption of p85α (p85 +/− heterozygous mice) were found to have a higher ratio of p85-p110 dimer to free p85 and to be more sensitive to insulin [9,[11][12][13][14][32][33][34]. In order to determine this ratio, the authors immunodepleted p110 and blotted both the immunoprecipitates and the supernatant with p85 antibody.…”

“…Thus, there is a balance between the free p85 monomer and the p85-p110 heterodimer, the latter being responsible for the PI 3-kinase activity. Increases or decreases in expression of p85 shift this balance in favour of either free p85 or p85-p110 complexes [11][12][13][14]. Because the monomer and the heterodimer compete for the same binding sites on the IRS proteins, an imbalance could cause either increased or decreased PI 3-kinase activity.…”