Phosphatidylinositol 3-kinase (PI 3-k) plays a critical role in mediating metabolic signaling of insulin. PI 3-k consists of a regulatory p85 (with p85α being the major isoform) and a catalytic p110 subunits. The regulatory subunit p85 exists in excess to p110, creating a certain balance between the free p85 monomer and a p85-p110 heterodimer complex that possesses PI 3-k activity. Because p85 monomer competes with the heterodimer for the IRS-1 binding sites, increases in p85 expression displace p85-p110 heterodimer from IRS-1, resulting in a decreased PI 3-k activity. This can occur in type 2 diabetes, obesity, and pregnancy, when insulin resistance is induced by human placental growth hormone (GH). In this study we tested the direct effect of GH on p85a expression in 3T3-L1 cells and in fat cells obtained from wild-type (WT) mice and mice with heterozygous deletion of p85α+/-.
Results Incubation of 3T3-L1 pre-adipocytes with increasing concentrations of rat recombinant GH (0, 500, and 2,500 ng/mL) for 24 hr increased p85α protein expression by approximately 250% (p < .001). In contrast, expression of p110 was not affected. In vivo insulin injection (10 U/kg BW) activated PI 3-k in the epididymal fat of WT and p85α+/- mice (p < .01). Administration of GH for 3 days (1 mg/kg s/c twice daily) blocked insulin-stimulated IRS-1-associated PI 3-k activity in the WT but not in p85α+/- mice.
Conclusions GH induces insulin resistance by increasing expression of p85α and creating an imbalance between the subunits of PI 3-k. Increases in p85α compete with p85-p110 heterodimer at the IRS-1 binding sites, resulting in decreased PI 3-k activity.
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