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Inactivation of the Class II PI3K-C2β Potentiates Insulin Signaling and Sensitivity

Alliouachene, S; Bilanges, B; Chicanne, G; Anderson, KE; Pearce, W; Ali, K; Valet, C; ... Vanhaesebroeck, B; + view all (2015) Inactivation of the Class II PI3K-C2β Potentiates Insulin Signaling and Sensitivity. Cell Reports , 13 (9) pp. 1881-1894. 10.1016/j.celrep.2015.10.052. Green open access

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Abstract

In contrast to the class I phosphoinositide 3-kinases (PI3Ks), the organismal roles of the kinase activity of the class II PI3Ks are less clear. Here, we report that class II PI3K-C2β kinase-dead mice are viable and healthy but display an unanticipated enhanced insulin sensitivity and glucose tolerance, as well as protection against high-fat-diet-induced liver steatosis. Despite having a broad tissue distribution, systemic PI3K-C2β inhibition selectively enhances insulin signaling only in metabolic tissues. In a primary hepatocyte model, basal PI3P lipid levels are reduced by 60% upon PI3K-C2β inhibition. This results in an expansion of the very early APPL1-positive endosomal compartment and altered insulin receptor trafficking, correlating with an amplification of insulin-induced, class I PI3K-dependent Akt signaling, without impacting MAPK activity. These data reveal PI3K-C2β as a critical regulator of endosomal trafficking, specifically in insulin signaling, and identify PI3K-C2β as a potential drug target for insulin sensitization.

Type: Article
Title: Inactivation of the Class II PI3K-C2β Potentiates Insulin Signaling and Sensitivity
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.celrep.2015.10.052
Publisher version: http://dx.doi.org/10.1016/j.celrep.2015.10.052
Language: English
Additional information: This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/1474618
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