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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Aims/hypothesis: Adiponectin is upregulated during adipogenesis and downregulated in insulin-resistant states. The mechanism(s) governing the re-arrangements from adipogenesis to facilitated lipolysis during pregnancy are unknown. Our purpose was to analyse the role of adiponectin relative to the metabolic changes in human pregnancy. Subjects, materials and methods: Lean women (BMI <25 kg/m²) were evaluated longitudinally before conception, and in early (12-14 weeks) and late (34-36 weeks) pregnancy. Insulin sensitivity was measured using the glucose clamp technique. Venous blood and subcutaneous adipose tissue biopsies were obtained at each time point. Results: Adiponectin concentrations were lower in the third trimester than in the pregravid condition (9.9±1.4 vs 13.5±1.8 μg/ml). The hypoadiponectinaemia was reflected by a 2.5-fold decrease in white adipose tissue adiponectin mRNA. These changes were associated with a 25% increase in fat mass (23.7±2.9 vs 18.9±2.9 kg). Insulin infusion decreased high molecular weight adiponectin complexes in pregravid women (9.9±0.6 vs 6.2±0.06) and the suppressive effect of insulin was lost during pregnancy. The pregnancy-mediated changes in adiponectin were strongly correlated with basal insulin levels and insulin sensitivity (p<0.0001). The relationship between adiponectin and insulin sensitivity was related to the decreased insulin regulation of glucose utilisation (r=0.55, p<0.001) but not of endogenous hepatic glucose production. Conclusions/interpretation: These data demonstrate that pregnancy is associated with adiponectin changes in lean women. Hypoadiponectinaemia is reflected by a lower amount of high molecular weight adiponectin and by the ratio of high to low molecular weight multimers. The adiponectin changes relate to decreased insulin sensitivity of glucose disposal rather than alterations of lipid metabolism.

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OBJECTIVE -We examined whether selected indexes of insulin sensitivity derived from an oral glucose tolerance test (IS OGTT ) or fasting glucose/insulin levels (IS QUICKI and IS HOMA ) can be used to predict insulin sensitivity in women before and during pregnancy. RESEARCH DESIGN AND METHODS -A 2-h euglycemic-hyperinsulinemic clamp(5 mmol/l glucose, 40 mU ⅐ m Ϫ2 ⅐ min Ϫ1 insulin) and a 120-min oral glucose tolerance test (75 g load pregravid, 100 g pregnant) were repeated on 15 women (10 with normal glucose tolerance [NGT] and 5 with gestational diabetes mellitus [GDM]) pregravid and during both early (12-14 weeks) and late (34 -36 weeks) pregnancy. An index of insulin sensitivity derived from the clamp (IS CLAMP ) was obtained from glucose infusion rates adjusted for change in fat-free mass and endogenous glucose production measured using [6,6-2 H 2 ]glucose.RESULTS -Univariate analysis using combined groups and periods of pregnancy resulted in significant correlations between IS CLAMP and IS OGTT (r 2 ϭ 0.74, P Ͻ 0.0001), IS QUICKI (r 2 ϭ 0.64, P Ͻ 0.0001), and IS HOMA (r 2 ϭ 0.53, P Ͻ 0.0001). The IS OGTT provided a significantly better correlation (P Ͻ 0.0001) than either IS QUICKI or IS HOMA. Multivariate analysis showed a significant group effect (P Ͻ 0.0003) on the prediction model, and separate equations were developed for the NGT (r 2 ϭ 0.64, P Ͻ 0.0001) and GDM (r 2 ϭ 0.85, P Ͻ 0.0001) groups. When subdivided by period of pregnancy, the correlation between IS CLAMP and IS OGTT pregravid was r 2 ϭ 0.63 (P ϭ 0.0002), during early pregnancy was r 2 ϭ 0.80 (P Ͻ 0.0001), and during late pregnancy was r 2 ϭ 0.64 (P ϭ 0.0002).CONCLUSIONS -Estimates of insulin sensitivity from the IS OGTT during pregnancy were significantly better than from fasting glucose and insulin values. However, separate prediction equations are necessary for pregnant women with NGT and women with GDM. Diabetes Care 24:1602-1607, 2001A number of standard clinical procedures are available for evaluating maternal insulin sensitivity during pregnancy, including the euglycemichyperinsulinemic clamp, the oral glucose tolerance test (OGTT), the intravenous glucose tolerance test, the Minimal Model, and various derivations of fasting glucose and insulin levels. The euglycemic-hyperinsulinemic clamp is considered by many the "gold standard" among these procedures (1). Although the clamp method can provide a precise measure of insulin sensitivity under physiological conditions, it is a relatively complicated and labor-intensive procedure and is not suitable for large-scale clinical or epidemiological studies. Therefore, a simple but valid estimate of insulin sensitivity is desirable to monitor and possibly reduce the potential adverse effects associated with hyperinsulinemia and/or hyperglycemia during pregnancy.In a recent report, Matsuda and DeFronzo (2) validated an index of insulin sensitivity estimated from glucose and insulin levels during an OGTT (IS OGTT ) against the clamp procedure. Katz et al. (3) have also validated an index of insul...

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Fetal overgrowth and higher adiposity are hallmarks of pregnancy with maternal obesity and poor glucose tolerance, two conditions associated with decreased maternal insulin sensitivity. In non-pregnant individuals, adipokines, vasoactive peptides, and components of the immune system crosstalk with metabolic factors to generate signals triggering obesity and impaired insulin action. We have investigated circulating maternal and fetal cytokines and growth-factors as potential biochemical markers of fetal adiposity. Mothers and neonates were classified into three tertiles (T1-T3) using total neonatal fat mass as the outcome with 309 +/- 25 g in T1, 478 +/- 40 g in T2, and 529 +/- 39 g in T3. Umbilical cord endothelin-1 (ET-1), C-peptide, and leptin were higher in T3 and T2 versus T1. Only cord leptin was strongly associated with fetal fat mass (P < .01), whereas neonatal lean body mass was negatively correlated with maternal insulin-like growth factor binding protein-I (IGFBP-I) (r = -0.53, P < .04). This study shows an association between increased fetal adiposity and maternal systemic interleukin-6 (IL-6). No such correlation was found with factors circulating in cord blood, suggesting that the stimuli favoring fetal fat accretion derive from maternal or placental sources rather than from the fetus.