Reduced expression of the murine p85α subunit of phosphoinositide 3-kinase improves insulin signaling and ameliorates diabetes
Franck Mauvais-Jarvis, Kohjiro Ueki, David A. Fruman, Michael F. Hirshman, Kei Sakamoto, Laurie J. Goodyear, Matteo Iannacone, Domenico Accili, Lewis C. Cantley, C. Ronald Kahn
Franck Mauvais-Jarvis, Kohjiro Ueki, David A. Fruman, Michael F. Hirshman, Kei Sakamoto, Laurie J. Goodyear, Matteo Iannacone, Domenico Accili, Lewis C. Cantley, C. Ronald Kahn
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Article

Reduced expression of the murine p85α subunit of phosphoinositide 3-kinase improves insulin signaling and ameliorates diabetes

Abstract

A critical component of insulin action is the enzyme phosphoinositide (PI) 3-kinase. The major regulatory subunits of PI 3-kinase, p85α and its splice variants, are encoded by the Pik3r1 gene. Heterozygous disruption of Pik3r1 improves insulin signaling and glucose homeostasis in normal mice and mice made insulin-resistant by heterozygous deletion of the Insulin receptor and/or insulin receptor substrate-1 (IRS1) genes. Reduced expression of p85 modulates the molecular balance between this protein, the p110 catalytic subunit of PI 3-kinase, and the IRS proteins. Thus, despite the decrease in p85α, PI 3-kinase activation is normal, insulin-stimulated Akt activity is increased, and glucose tolerance and insulin sensitivity are improved. Furthermore, Pik3r1 heterozygosity protects mice with genetic insulin resistance from developing diabetes. These data suggest that regulation of p85α levels may provide a novel therapeutic target for the treatment of type 2 diabetes.

Authors

Franck Mauvais-Jarvis, Kohjiro Ueki, David A. Fruman, Michael F. Hirshman, Kei Sakamoto, Laurie J. Goodyear, Matteo Iannacone, Domenico Accili, Lewis C. Cantley, C. Ronald Kahn

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Figure 3

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PI 3-kinase activation in liver and muscle of Pik3r1 mutant mice. Lysate...
PI 3-kinase activation in liver and muscle of Pik3r1 mutant mice. Lysates from the liver of animals were immunoprecipitated with the indicated antibodies and subjected to a PI 3-kinase assay as described in Methods. PI 3-kinase activities associated with total regulatory subunit (αp85pan) (a), associated with p85α regulatory subunit (αp85α) (b), associated with the p110 catalytic subunit (αp110) (c), associated with tyrosine-phosphorylated proteins (αPY) (d), and associated with p85β regulatory subunit (αp85β) (e) were assessed. The upper panels shows representative PI 3-kinase assays, while each bar in the lower panels represents the mean ± SEM of the relative PI 3-kinase activity (% of unstimulated wild-type) calculated from at least three independent experiments. *P < 0.05, wild-type vs. p85+/–. (f) Activation of PI 3-kinase in muscle. Lysates were immunoprecipitated with the p85pan antibody (αp85pan, top panel), tyrosine-phosphorylated proteins (αPY, middle panel), or the p85β regulatory subunit (αp85β, bottom panel), and subjected to PI 3-kinase assay as above.