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TNF- Is a Predictor of Insulin Resistance in Human Pregnancy

¹ Department of Reproductive Biology, Case Western Reserve University School of Medicine at MetroHealth Medical Center, Cleveland, Ohio
² Department of Nutrition, Case Western Reserve University School of Medicine at MetroHealth Medical Center, Cleveland, Ohio
³ Département d’Endocrinologie, Institut Cochin de Génétique Moléculaire, Paris, France
⁴ Service de Gynécologie-Obstétrique, Hôpital Cochin-Saint Vincent-de-Paul, Paris, France
⁵ Departments of Pediatrics, Biochemistry, and Molecular Genetics, University of Colorado Health Sciences Center, Denver, Colorado
⁶ Schwartz Center for Metabolism and Nutrition, Case Western Reserve University School of Medicine at MetroHealth Medical Center, Cleveland, Ohio

Historically, insulin resistance during pregnancy has been ascribed to increased production of placental hormones and cortisol. The purpose of this study was to test this hypothesis by correlating the longitudinal changes in insulin sensitivity during pregnancy with changes in placental hormones, cortisol, leptin, and tumor necrosis factor (TNF)-. Insulin resistance was assessed in 15 women (5 with gestational diabetes mellitus [GDM] and 10 with normal glucose tolerance) using the euglycemic-hyperinsulinemic clamp procedure, before pregnancy (pregravid) and during early (12–14 weeks) and late (34–36 weeks) gestation. Body composition, plasma TNF-, leptin, cortisol, and reproductive hormones (human chorionic gonadotropin, estradiol, progesterone, human placental lactogen, and prolactin) were measured in conjunction with the clamps. Placental TNF- was measured in vitro using dually perfused human placental cotyledon from five additional subjects. Compared with pregravid, insulin resistance was evident during late pregnancy in all women (12.4 ± 1.2 vs. 8.1 ± 0.8 10^-2 mg · kg^-1 fat-free mass · min^-1 · µU^-1 · ml^-1). TNF-, leptin, cortisol, all reproductive hormones, and fat mass were increased in late pregnancy (P < 0.001). In vitro, most of the placental TNF- (94%) was released into the maternal circulation; 6% was released to the fetal side. During late pregnancy, TNF- was inversely correlated with insulin sensitivity (r = -0.69, P < 0.006). Furthermore, among all of the hormonal changes measured in this study, the change in TNF- from pregravid to late pregnancy was the only significant predictor of the change in insulin sensitivity (r = -0.60, P < 0.02). The placental reproductive hormones and cortisol did not correlate with insulin sensitivity in late pregnancy. Multivariate stepwise regression analysis revealed that TNF- was the most significant independent predictor of insulin sensitivity (r = -0.67, P < 0.0001), even after adjustment for fat mass by covariance (r = 0.46, P < 0.01). These observations challenge the view that the classical reproductive hormones are the primary mediators of change in insulin sensitivity during gestation and provide the basis for including TNF- in a new paradigm to explain insulin resistance in pregnancy.

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