This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kirwan, J. P. Articles by Catalano, P. M. Search for Related Content PubMed PubMed Citation Articles by Kirwan, J. P. Articles by Catalano, P. M.

Reversal of Insulin Resistance Postpartum Is Linked to Enhanced Skeletal Muscle Insulin Signaling

Departments of Reproductive Biology (J.P.K., A.V., M.J., L.P., P.M.C.) and Nutrition (J.P.K.), Case Western Reserve University School of Medicine, and Schwartz Center for Metabolism and Nutrition (J.P.K., P.M.C.), MetroHealth Medical Center, Cleveland, Ohio 44109; and Departments of Pediatrics, Biochemistry, and Molecular Genetics (J.S., J.E.F.), University of Colorado Health Sciences Center, Denver, Colorado 80262

Address all correspondence and requests for reprints to: Jacob E. Friedman, Ph.D., Departments of Pediatrics, Biochemistry, and Molecular Genetics, University of Colorado Health Sciences Center, 4200 East 9th Avenue, B-195, Denver, Colorado 80262. E-mail: jed.friedman{at}uchsc.edu.

The restoration of maternal insulin sensitivity postpartum represents an important physiological and metabolic adaptation in a woman’s reproductive lifespan. The present study was conducted to examine the potential cellular mechanisms underlying the changes in insulin sensitivity from late pregnancy to postpartum in human skeletal muscle. Nine nonobese women (age, 32 ± 2 yr; body mass index, 21.2 ± 0.8 kg/m²) with normal glucose tolerance were studied during late pregnancy (30–36 wk) and again approximately 1 yr postpartum using a euglycemic-hyperinsulinemic clamp (5 mM glucose, 40 mU/m²·min insulin) to determine insulin sensitivity. Biopsies of the vastus lateralis muscle were obtained in the basal state before each clamp. Insulin sensitivity improved by 74% from late pregnancy to 1 yr postpartum (5.5 ± 0.6 vs. 9.6 ± 0.9 mg/kg fat-free mass·min; P < 0.005). Skeletal muscle insulin receptor (IR) protein expression increased by 42% postpartum, as measured by ELISA (4.0 ± 0.6 vs. 5.7 ± 0.6 ng/g protein; P < 0.05) and by Western blotting of the IR ß-subunit (28.7 ± 4.7 vs. 42.0 ± 4.8 arbitrary units; P < 0.003). However, in vitro studies showed that when adjusted for IR concentration, maximal insulin-stimulated (100 nM) IR tyrosine phosphorylation (0.75 ± 0.06 vs. 0.92 ± 0.08 U) and IR tyrosine kinase activity (183.8 ± 27.0 vs. 204.3 ± 23.7 fmol ATP/ng IR) were unchanged. There was a 69% increase in IR substrate-1 (IRS-1) protein expression (P = 0.05) in muscle postpartum. In addition, the p85 regulatory subunit of phosphatidylinositol 3-kinase was markedly reduced by 55% (P < 0.02) postpartum. The change in insulin sensitivity from late pregnancy to postpartum correlated highly with the corresponding change in IRS-1 protein (r = 0.84; P < 0.007). Downstream signaling proteins, including total Akt and p70s6 kinase, and the glucose transporter protein GLUT-4, were similar at both time points. These data suggest that reduced IR tyrosine kinase activity is not a major factor in the IR of pregnancy in lean women with normal glucose tolerance. Rather, the reversal of insulin resistance 1 yr postpartum is accompanied by increased skeletal muscle IRS-1 along with a down-regulation of the p85 subunit of phosphatidylinositol 3-kinase. These changes may allow for greater p85/p110 binding to IRS-1 and play a significant physiological role in the underlying metabolic adaptation to normal human pregnancy and restoration of insulin sensitivity postpartum.

This article has been cited by other articles:

				J. E. Friedman, J. P. Kirwan, M. Jing, L. Presley, and P. M. Catalano Increased Skeletal Muscle Tumor Necrosis Factor-{alpha} and Impaired Insulin Signaling Persist in Obese Women With Gestational Diabetes Mellitus 1 Year Postpartum Diabetes, March 1, 2008; 57(3): 606 - 613. [Abstract] [Full Text] [PDF]

				L. A. Barbour, C. E. McCurdy, T. L. Hernandez, J. P. Kirwan, P. M. Catalano, and J. E. Friedman Cellular Mechanisms for Insulin Resistance in Normal Pregnancy and Gestational Diabetes Diabetes Care, July 1, 2007; 30(Supplement_2): S112 - S119. [Full Text] [PDF]

				C. C. Connolly, T. Papa, M. S. Smith, D. B. Lacy, P. E. Williams, and M. C. Moore Hepatic and muscle insulin action during late pregnancy in the dog Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2007; 292(1): R447 - R452. [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]

				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. 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]

				M. Milanski, V. C. Arantes, F. Ferreira, M. A. d. B. Reis, E. M. Carneiro, A. C. Boschero, C. B. Collares-Buzato, and M. Q. Latorraca Low-Protein Diets Reduce PKA{alpha} Expression in Islets from Pregnant Rats J. Nutr., August 1, 2005; 135(8): 1873 - 1878. [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]

				R. Sancho, J. Kim, and G. D. Cartee Decreased contraction-stimulated glucose transport in isolated epitrochlearis muscles of pregnant rats J Appl Physiol, March 1, 2005; 98(3): 1021 - 1027. [Abstract] [Full Text] [PDF]