Reduced expression of the murine p85α subunit of phosphoinositide 3-kinase improves insulin signaling and ameliorates diabetes
Franck Mauvais-Jarvis, … , Lewis C. Cantley, C. Ronald Kahn
Franck Mauvais-Jarvis, … , Lewis C. Cantley, C. Ronald Kahn
Published January 1, 2002
Citation Information: J Clin Invest. 2002;109(1):141-149. https://doi.org/10.1172/JCI13305.
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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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Signaling molecules involved in activation of PI 3-kinase by insulin. (a...
Signaling molecules involved in activation of PI 3-kinase by insulin. (a) Expression levels of Pik3r1 gene products were determined in lysates from liver (left) and skeletal muscle (right) by Western blotting with an anti-p85pan antibody (αp85pan). (b) Tyrosine phosphorylation of IRS proteins and association with p85 were determined using lysates from liver of the indicated animals. Proteins were immunoprecipitated with anti–IRS-1 antibody (αIRS-1) (top two panels) or anti–IRS-2 antibody (αIRS-2) (bottom two panels), and blotted with anti-phosphotyrosine antibody (αPY) or αp85pan. (c) To determine the molecular balance between p85 and p110, the liver lysates were subjected to three sequential rounds of immunodepletion using αp110, followed by Western blotting with αp110 (left top panel) or αp85pan (left bottom panel). The amount of the p85-p110 dimer and the p85 monomer was expressed as the ratio to the value of the amount of the p85 monomer in the wild-type cells. In the graph, each bar represents the ratio to the total p85 in wild-type cells (open bar, p85-p110 dimer; dotted bar, p85 monomer).