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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.

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