title: TNF-alpha is a predictor of insulin resistance in human pregnancy.
abstract: 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)-alpha. 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-alpha, leptin, cortisol, and reproductive hormones (human chorionic gonadotropin, estradiol, progesterone, human placental lactogen, and prolactin) were measured in conjunction with the clamps. Placental TNF-alpha 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). microU(-1). ml(-1)). TNF-alpha, leptin, cortisol, all reproductive hormones, and fat mass were increased in late pregnancy (P < 0.001). In vitro, most of the placental TNF-alpha (94%) was released into the maternal circulation; 6% was released to the fetal side. During late pregnancy, TNF-alpha 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-alpha 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-alpha 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-alpha in a new paradigm to explain insulin resistance in pregnancy.
authors.affiliation: Department of Reproductive Biology, Case Western Reserve University School of Medicine at MetroHealth Medical Center, Bell Greve Building Rm. G-232E, 2500 MetroHealth Drive, Cleveland, OH 44109-1998, USA. jpk10@po.cwru.edu
authors.forename: John P
authors.initials: JP
authors.lastname: Kirwan
authors.forename: Sylvie
authors.initials: S
authors.lastname: Hauguel-De Mouzon
authors.forename: Jacques
authors.initials: J
authors.lastname: Lepercq
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Challier
authors.forename: Larraine
authors.initials: L
authors.lastname: Huston-Presley
authors.forename: Jacob E
authors.initials: JE
authors.lastname: Friedman
authors.forename: Satish C
authors.initials: SC
authors.lastname: Kalhan
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Catalano
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000378:metabolism*; D001823:Body Composition; D006063:Chorionic Gonadotropin / Q000097:blood; D016640:Diabetes, Gestational / Q000097:blood*; D005260:Female; D005865:Gestational Age; D015309:Glucose Clamp Technique; D018149:Glucose Intolerance / Q000097:blood*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007262:Infusions, Intravenous; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology; D007333:Insulin Resistance; D020738:Leptin / Q000097:blood; D010920:Placenta / Q000502:physiology; D010928:Placental Lactogen / Q000097:blood; D011237:Predictive Value of Tests; D011247:Pregnancy / Q000097:blood / Q000502:physiology*; D011388:Prolactin / Q000097:blood; D012016:Reference Values; D012044:Regression Analysis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D006063:Chorionic Gonadotropin; D007328:Insulin; D020738:Leptin; D014409:Tumor Necrosis Factor-alpha; D011388:Prolactin; D010928:Placental Lactogen; D006854:Hydrocortisone