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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Increased insulin sensitivity in the Pik3r1 mutant groups. (a) Insulin t...
Increased insulin sensitivity in the Pik3r1 mutant groups. (a) Insulin tolerance tests (1 U/kg, intraperitoneally) and (b) IGF-1 tolerance tests (1 mg/kg, intraperitoneally) were performed on 6-month-old male mice of the indicated genotypes. Results represent the blood glucose concentration as a percentage of the starting glucose value and are expressed as mean ± SEM (n = 12–30 mice per genotype). *P < 0.05, wild-type vs. p85+/–; IR+/– vs. IR/p85+/–; IR/IRS-1+/– vs. IR/IRS-1/p85+/–. (c) Glucose transport activity in isolated skeletal muscle of the Pik3r1 mutant mice was estimated using 2-deoxyglucose uptake in isolated EDL and soleus muscles as described in Methods. Results are expressed as mean ± SEM (n = 4). *P < 0.05, wild-type vs. p85+/–.