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

A critical component of insulin action is the enzyme phosphoinositide (PI) 3-kinase. The major regulatory subunits of PI 3-kinase, p85 alpha and its splice variants, are encoded by the Pik3r1 gene. Heterozygous disruption of Pik3r1 improves insulin signaling and glucose homeostasis in normal mice an...

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Bibliographic Details
Published in:The Journal of clinical investigation 2002-01, Vol.109 (1), p.141-149
Main Authors: Mauvais-Jarvis, Franck, Ueki, Kohjiro, Fruman, David A., Hirshman, Michael F., Sakamoto, Kei, Goodyear, Laurie J., Iannacone, Matteo, Accili, Domenico, Cantley, Lewis C., Kahn, C. Ronald
Format: Article
Language:English
Subjects:
Akt protein
IRS1 gene
p85 protein
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Summary:A critical component of insulin action is the enzyme phosphoinositide (PI) 3-kinase. The major regulatory subunits of PI 3-kinase, p85 alpha 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 p85 alpha , 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 p85 alpha levels may provide a novel therapeutic target for the treatment of type 2 diabetes.
ISSN:0021-9738
DOI:10.1172/JCI0213305