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 ⅐ kg ؊1 fat-free mass ⅐ min ؊1 ⅐ U ؊1 ⅐ 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. Diabetes 51:2207-2213, 2002

Background: Childhood obesity has increased significantly in recent decades. Objective: The objective was to examine the perinatal risk factors related to childhood obesity. Design: In a prospective study, 89 women with normal glucose tolerance (NGT) or gestational diabetes mellitus (GDM) and their offspring were evaluated at birth and at 8.8 6 1.8 y. At birth, obstetrical data, parental anthropometric measures, and neonatal body composition were assessed; at follow-up, diet and activity were assessed and laboratory studies were conducted. Weight was classified by using weight for age and sex, and body composition was measured by using dual-energy X-ray absorptiometry. In childhood, data were analyzed as tertiles and prediction models were developed by using logistic and stepwise regression. Results: No significant differences in Centers for Disease Control and Prevention weight percentiles, body composition, and most metabolic measures were observed between children of mothers with NGT and GDM at follow-up. Children in the upper tertile for weight had greater energy intake (P = 0.02), skinfold thickness (P = 0.0001), and leptin concentrations (P , 0.0001) than did those in tertiles 1 and 2. Children in the upper tertile for percentage body fat had greater waist circumference (P = 0.0001), insulin resistance (P = 0.002), and triglyceride (P = 0.009) and leptin (P = 0.0001) concentrations than did children in tertiles 1 and 2. The correlation between body fat at birth and follow-up was r = 0.29 (P = 0.02). The strongest perinatal predictor for a child in the upper tertile for weight was maternal pregravid body mass index (BMI; kg/m 2 ) .30 (odds ratio: 3.75; 95% CI: 1.39, 10.10; P = 0.009) and for percentage body fat was maternal pregravid BMI .30 (odds ratio: 5.45; 95% CI: 1.62, 18.41; P = 0.006). Conclusion: Maternal pregravid BMI, independent of maternal glucose status or birth weight, was the strongest predictor of childhood obesity.

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