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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
Abstract
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 p85α 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 p85α monomer, which competes in a dominant negative fashion with the p85-p110 heterodimer for binding to IRS-1 protein.
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“Later in pregnancy, a state of insulin resistance develops in the peripheral maternal tissues, mediated, in part, through the actions of placental growth hormone (23).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [23]
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Metadata
- Authors
- Barbour, L. A., Shao, J., Qiao, L., Leitner, W., Anderson, M., Friedman, J. E., & Draznin, B.
- Affiliations
- Department of Medicine (L.A.B., B.D.), Denver, Colorado 80262
- Department of Pediatrics (J.S., L.Q., M.A., J.E.F.), Denver, Colorado 80262
- University of Colorado Health (US)
- Corresponding author
- Barbour, Linda A.
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2004-03-01
- Volume
- 145
- Issue
- 3
- Pages
- 1144-1150
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- OpenAlex
- W2111953703
- Cited by
- 208
- References
- 27
- Citations by year
- 2025: 4 · 2024: 4 · 2023: 24 · 2022: 6 · 2021: 10 · 2020: 12 · 2019: 12 · 2018: 8 · 2017: 6 · 2016: 6 · 2015: 11 · 2014: 6 · 2013: 6 · 2012: 13
- FWCI
- 5.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01dk062155-04)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-62155)
- National Center for Research Resources (K23RR017496, 1K23-RR-017496-01)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Obstetrics and Gynecology › Gestational Diabetes Research and Management
- Keywords
- placental growth hormone, insulin resistance, skeletal muscle, phosphatidylinositol 3-kinase, IRS-1, GLUT4 translocation, insulin receptor, p110 catalytic subunit, transgenic mice, pregnancy, dominant negative regulation, insulin signaling
- MeSH terms
- Placenta Growth Factor, Animals, Cell Membrane, Humans, Insulin Resistance, Mice, Transgenic, Monosaccharide Transport Proteins, Muscle Proteins, Phosphoproteins, Phosphorylation, Pregnancy Proteins, Receptor, Insulin, Signal Transduction, Protein Structure, Tertiary, Muscle, Skeletal, Phosphatidylinositol 3-Kinases, Glucose Transporter Type 4, Mice, Insulin Receptor Substrate Proteins
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