| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on September 29, 2003
Accepted on November 11, 2003
1 Departments of Medicine, Obstetrics and Gynecology, and Pediatrics, University of Colorado Health Sciences Center and the Research Service of the Denver Veterans Affairs Medical Center
* To whom correspondence should be addressed. 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 growth hormone (hPGH) can trigger severe insulin resistance in transgenic (TG) mice and in this paper, 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 the wild-type (WT) mice (P = 0.05). Insulin receptor (IR) levels were modestly reduced by 19% (P < 0.01) in the TG mice but there were no changes in phosphorylation of IR or IRS-1 between WT and TG mice. A singular finding was a highly significant increase in the p85
regulatory subunit of 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 hPGH may contribute to the insulin resistance of normal pregnancy by increasing expression of the p85 monomer which competes in a dominant negative fashion with the p85-p110 heterodimer for binding to IRS-1 protein.
This article has been cited by other articles:
 |
|
 |
|
  R. Arumugam, E. Horowitz, D. Lu, J. J. Collier, S. Ronnebaum, D. Fleenor, and M. Freemark The Interplay of Prolactin and the Glucocorticoids in the Regulation of {beta}-Cell Gene Expression, Fatty Acid Oxidation, and Glucose-Stimulated Insulin Secretion: Implications for Carbohydrate Metabolism in Pregnancy Endocrinology, November 1, 2008; 149(11): 5401 - 5414. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-P. del Rincon, K. Iida, B. D. Gaylinn, C. E. McCurdy, J. W. Leitner, L. A. Barbour, J. J. Kopchick, J. E. Friedman, B. Draznin, and M. O. Thorner Growth Hormone Regulation of p85{alpha} Expression and Phosphoinositide 3-Kinase Activity in Adipose Tissue: Mechanism for Growth Hormone-Mediated Insulin Resistance Diabetes, June 1, 2007; 56(6): 1638 - 1646. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Taniguchi, T. T. Tran, T. Kondo, J. Luo, K. Ueki, L. C. Cantley, and C. R. Kahn Phosphoinositide 3-kinase regulatory subunit p85{alpha} suppresses insulin action via positive regulation of PTEN PNAS, August 8, 2006; 103(32): 12093 - 12097. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Draznin Molecular Mechanisms of Insulin Resistance: Serine Phosphorylation of Insulin Receptor Substrate-1 and Increased Expression of p85{alpha}: The Two Sides of a Coin. Diabetes, August 1, 2006; 55(8): 2392 - 2397. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Kobayashi, Y. Hayashi, K. Taguchi, T. Matsumoto, and K. Kamata ANG II enhances contractile responses via PI3-kinase p110{delta} pathway in aortas from diabetic rats with systemic hyperinsulinemia Am J Physiol Heart Circ Physiol, August 1, 2006; 291(2): H846 - H853. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Huo, R. C. McEachin, T. X. Cui, N. K. Duggal, T. Hai, D. J. States, and J. Schwartz Profiles of Growth Hormone (GH)-regulated Genes Reveal Time-dependent Responses and Identify a Mechanism for Regulation of Activating Transcription Factor 3 By GH J. Biol. Chem., February 17, 2006; 281(7): 4132 - 4141. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Barbour, S. Mizanoor Rahman, I. Gurevich, J. W. Leitner, S. J. Fischer, M. D. Roper, T. A. Knotts, Y. Vo, C. E. McCurdy, S. Yakar, et al. Increased P85{alpha} Is a Potent Negative Regulator of Skeletal Muscle Insulin Signaling and Induces in Vivo Insulin Resistance Associated with Growth Hormone Excess J. Biol. Chem., November 11, 2005; 280(45): 37489 - 37494. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. G. Miquet, A. I. Sotelo, A. Bartke, and D. Turyn Desensitization of the JAK2/STAT5 GH signaling pathway associated with increased CIS protein content in liver of pregnant mice Am J Physiol Endocrinol Metab, October 1, 2005; 289(4): E600 - E607. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. Batista, M. S. Smith, W. L. Snead, C. C. Connolly, D. B. Lacy, and M. C. Moore Chronic estradiol and progesterone treatment in conscious dogs: effects on insulin sensitivity and response to hypoglycemia Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2005; 289(4): R1064 - R1073. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Luo, S. J. Field, J. Y. Lee, J. A. Engelman, and L. C. Cantley The p85 regulatory subunit of phosphoinositide 3-kinase down-regulates IRS-1 signaling via the formation of a sequestration complex J. Cell Biol., August 1, 2005; 170(3): 455 - 464. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. K. Bandyopadhyay, J. G. Yu, J. Ofrecio, and J. M. Olefsky Increased p85/55/50 Expression and Decreased Phosphotidylinositol 3-Kinase Activity in Insulin-Resistant Human Skeletal Muscle Diabetes, August 1, 2005; 54(8): 2351 - 2359. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Gavete, M. A. Martin, C. Alvarez, and F. Escriva Maternal Food Restriction Enhances Insulin-Induced GLUT-4 Translocation and Insulin Signaling Pathway in Skeletal Muscle from Suckling Rats Endocrinology, August 1, 2005; 146(8): 3368 - 3378. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-C. Lacroix, J. Guibourdenche, T. Fournier, I. Laurendeau, A. Igout, V. Goffin, J. Pantel, V. Tsatsaris, and D. Evain-Brion Stimulation of Human Trophoblast Invasion by Placental Growth Hormone Endocrinology, May 1, 2005; 146(5): 2434 - 2444. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Sadagurski, G. Weingarten, C. J. Rhodes, M. F. White, and E. Wertheimer Insulin Receptor Substrate 2 Plays Diverse Cell-specific Roles in the Regulation of Glucose Transport J. Biol. Chem., April 15, 2005; 280(15): 14536 - 14544. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Brachmann, K. Ueki, J. A. Engelman, R. C. Kahn, and L. C. Cantley Phosphoinositide 3-Kinase Catalytic Subunit Deletion and Regulatory Subunit Deletion Have Opposite Effects on Insulin Sensitivity in Mice Mol. Cell. Biol., March 1, 2005; 25(5): 1596 - 1607. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. P. Kirwan, A. Varastehpour, M. Jing, L. Presley, J. Shao, J. E. Friedman, and P. M. Catalano Reversal of Insulin Resistance Postpartum Is Linked to Enhanced Skeletal Muscle Insulin Signaling J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4678 - 4684. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
