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Human Placental Growth Hormone Increases Expression of the P85 Regulatory Unit of Phosphatidylinositol 3-Kinase and Triggers Severe Insulin Resistance in Skeletal Muscle

Departments of Medicine (L.A.B., B.D.), Obstetrics and Gynecology (L.A.B.), and Pediatrics (J.S., L.Q., M.A., J.E.F.), University of Colorado Health Sciences Center, and Research Service of the Denver Veterans Affairs Medical Center (W.L., B.D.), Denver, Colorado 80262

Address all correspondence and requests for reprints to: Linda A Barbour, M.D., University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Box B-198, Denver, Colorado 80262. E-mail: lynn.barbour{at}uchsc.edu.

The insulin resistance of normal pregnancy is necessary to divert fuels to the fetus to meet fetal growth demands and is mediated by placental hormones. We recently demonstrated that human placental GH (hPGH) can trigger severe insulin resistance in transgenic (TG) mice. In this study we sought to elucidate the cellular mechanisms by which hPGH interferes with insulin signaling in muscle in TG mice. Insulin-stimulated GLUT-4 translocation to the plasma membrane (PM) was reduced in the TG compared with wild-type (WT) mice (P = 0.05). Insulin receptor (IR) levels were modestly reduced by 19% (P < 0.01) in TG mice, but there were no changes in phosphorylation of IR or IR substrate-1 (IRS-1) between WT and TG mice. A singular finding was a highly significant increase in the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI 3-kinase; P < 0.001), yet a reduced ability of insulin to stimulate IRS-1-associated PI 3-kinase activity (P < 0.05). Although the levels of the p110 catalytic subunit protein of PI 3-kinase and IRS-1 were unchanged in the TG mice, insulin’s ability to stimulate p110 association with IRS-1 was markedly reduced (P < 0.0001). We demonstrate a unique mechanism of insulin resistance and suggest that hPGH may contribute to the insulin resistance of normal pregnancy by increasing the expression of the p85 monomer, which competes in a dominant negative fashion with the p85-p110 heterodimer for binding to IRS-1 protein.

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