Augmented insulin secretory response in early pregnancy.

AIMS/HYPOTHESIS: This study aimed to examine changes in the insulin secretory response in early pregnancy, while accounting for changes in insulin sensitivity. METHODS: This is a secondary analysis of a previously conducted longitudinal physiological study. In 34 women, insulin secretory response (by IVGTT) and insulin sensitivity (by euglycaemic clamp) were assessed prior to pregnancy, in early pregnancy (12-14 weeks gestation) and in late pregnancy (34-36 weeks gestation). Using mixed-effects models, we compared insulin secretory response and sensitivity in early pregnancy to the same variables prior to pregnancy and in late pregnancy, with adjustment for age, obesity status and gestational diabetes mellitus (GDM). We examined changes in insulin secretory response after adjustment for insulin sensitivity using both multivariate modelling and the disposition index (DI). We explored the relationship between insulin secretory response and circulating hormones. RESULTS: The insulin secretory response increased from prior to pregnancy to early pregnancy (unadjusted mean [SD] first-phase insulin response 465.1 [268.5] to 720 [358.2], p < 0.0001) and from early pregnancy to late pregnancy (to 924 [494.6], p = 0.01). Insulin sensitivity increased from prior to pregnancy to early pregnancy (insulin sensitivity index 0.10 [0.04] to 0.12 [0.05], p = 0.001) and decreased in late pregnancy (to 0.06 [0.03], p < 0.0001). Accounting for changes in insulin sensitivity, using either multivariate modelling or the DI, did not attenuate the early-pregnancy augmentation of insulin secretory response. Leptin was positively associated with insulin secretory response, independent of insulin sensitivity and adiposity (p = 0.004). Adjustment for leptin attenuated the observed augmentation of insulin secretory response in early pregnancy (adjusted mean change 121.5, p = 0.13). CONCLUSIONS/INTERPRETATION: The insulin secretory response increases markedly in early pregnancy, prior to and independent of changes in insulin sensitivity. Circulating hormones may mediate this metabolic adaptation. Identifying mediators of this physiological effect could have therapeutic implications for treating hyperglycaemia during and outside of pregnancy.

Does the dawn phenomenon have clinical relevance in normal pregnancy?

OBJECTIVE: The dawn phenomenon is a transient rise in blood glucose between 4 and 6 am that is attributed to the pulsatile release of pituitary growth hormone (GH). In pregnancy, GH is suppressed by placental GH. Hence, we hypothesize that there is no evidence for the dawn phenomenon in late pregnancy in healthy women. STUDY DESIGN: Twenty glucose-tolerant women with singleton gestations between 28 weeks and 36 weeks 6 days' gestation were recruited. The women were admitted overnight to the Clinical Research Unit and had continuous glucose monitoring. Insulin and GH were measured at 2-hour intervals from 8 pm to 8 am. GH was grouped into times 1A (8-10 pm), 2A (12-2 am), and 3A (4-8 am) for changes over time. Further analysis was performed with time 1B (8 pm to 2 am) and 2B (4-8 am). Insulin was measured between 4 and 8 am. RESULTS: Plasma glucose decreased over time (P < .001). There were no significant changes in GH among times 1A, 2A, and 3A (P = .45) or times 1B and 2B (P = .12). Insulin concentrations increased after meals, but there were no changes from 4 am (8.5 ± 1.4 µU/mL) through 8 am (8.6 ± 1.1 µU/mL; P = .98). CONCLUSION: Glucose and insulin concentrations show no increase from 4-8 am; although there is variability in GH, there is no evidence for the dawn phenomenon in late pregnancy in healthy women.

Neonatal body composition according to the revised institute of medicine recommendations for maternal weight gain.

BACKGROUND: In 2009, the Institute of Medicine (IOM) released revised pregnancy weight gain guidelines. There are limited data regarding the effect of maternal weight gain on newborn adiposity. OBJECTIVE: The aim of this study was to estimate neonatal fat mass, lean body mass, and percentage body fat according to current Institute of Medicine (IOM) pregnancy weight gain guidelines. DESIGN: This is a secondary analysis of a prospective observational cohort study of neonates delivered at least 36 wk gestation and evaluated for fat mass, lean body mass, and percentage body fat. Women with abnormal glucose tolerance testing and other known medical disorders or pregnancies with known fetal anomalies were excluded. Pregravid body mass index (BMI) was categorized as normal weight (<25 kg/m2), overweight (25-30 kg/m2), or obese (>30 kg/m2). Maternal weight gain was quantified as less than, equal to, or greater than current IOM guidelines. Newborn body composition measurements were compared according to weight gain and BMI categories. RESULTS: A total of 439 maternal-newborn pairs were evaluated; 19.8% (n=87) of women gained less than IOM guidelines; 31.9% (n=140), equal to IOM guidelines; and 48.3% (n=212), greater than IOM guidelines. Significant differences for each component of body composition were found when evaluated by IOM weight gain categories (all ANOVA, P<0.001). When controlling for pregravid BMI, only weight gain for women who were of normal weight before pregnancy remained significant. CONCLUSION: Maternal weight gain during pregnancy is a significant contributor to newborn body composition, particularly for women who are of normal weight before pregnancy.

Women's reported weight: is there a discrepancy?

OBJECTIVE: To compare self-reported pre-pregnancy weight & delivery weight with documented pre-pregnancy & delivery weight and determine whether there are differences compared with the Institute of Medicine's (IOM) guidelines. METHODS: This is a retrospective analysis of 234 women. Inclusion criteria included documented height, self-reported pre-pregnancy weight, self-reported delivery weight, documented pre-pregnancy weight ± 12 weeks from last menstrual period, and documented delivery weight ± 2 weeks from delivery. We determined the difference between self-reported pre-pregnancy weight vs. documented pre-pregnancy weight and self-reported delivery weight vs. documented delivery weight. Using documented pre-pregnancy weight and documented delivery weight, we calculated gestational weight gain (GWG) relative to IOM criteria. RESULTS: Self-reported pre-pregnancy weight was 2.94 kg less than documented pre-pregnancy weight (p < 0.0001). Self-reported BMI was 1.11 mg/kg(2) less than documented BMI (p < 0.0001). Self-reported GWG was 3.01 kg greater than documented GWG (p < 0.0001). Ninety-eight percent of normal weight correctly classified pregravid BMI in contrast to 86% of obese (p < 0.005) and 73% of overweight (p < 0.001). CONCLUSIONS: Overweight and obese women underestimated self-reported pre-pregnancy weight & overestimated GWG, thereby mistakenly categorizing IOM guidelines.

Birth weight and body composition of neonates born to Caucasian compared with African-American mothers.

OBJECTIVE: To estimate whether neonates of African-American women have lower birth weights because of either decreased lean body mass or fat mass. METHODS: A secondary analysis of a cohort of 104 African-American and 274 Caucasian term, singleton, healthy pregnancies. Women with existing or gestational diabetes were excluded. Neonatal body composition was estimated using anthropometric measurements. RESULTS: There were significant differences in maternal age (29.5 compared with 25.8, P<.001), prepregnancy body mass index (26.2 compared with 30.9 kg/m, P<.001), and weight gain during pregnancy (15.2 compared with 13.4 kg, P=.03) in Caucasian compared with African-American women, respectively. After adjusting for these factors, African-American women's neonates had significantly lower birth weights (3.20 compared with 3.36 kg, P=.003), less lean body mass (2.80 compared with 2.94 kg, P=.002), but no difference in fat mass (392 compared with 417 g, P=.078). CONCLUSION: Decreased birth weight in African-American neonates is due to lower lean body mass and not a difference in adiposity.

Estimates of insulin sensitivity using glucose and C-Peptide from the hyperglycemia and adverse pregnancy outcome glucose tolerance test.

OBJECTIVE To determine if glucose and C-peptide values obtained as part of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study could be used to estimate insulin sensitivity during late pregnancy. RESEARCH DESIGN AND METHODS A total of 78 women enrolled in the HAPO study were recruited for this ancillary study. Venous plasma samples were drawn after an 8- to 10-h fast (time 0) and at 30, 60, 90, and 120 min after a 75-g glucose challenge, which was performed at 24-32 weeks' gestation. Samples were analyzed for plasma glucose, insulin, and C-peptide. Insulin sensitivity was estimated using the established Matsuda and DeFronzo insulin sensitivity index for oral glucose tolerance tests (IS(OGTT)). Insulin sensitivity was also calculated from two other commonly used indexes of insulin sensitivity (that for homeostasis model assessment [IS(HOMA)] and that for quantitative insulin sensitivity check index [IS(QUICKI)]). A new insulin sensitivity index was calculated using the glucose and C-peptide concentrations at 0 and 60 min to derive IS(HOMA C-pep), IS(QUICKI C-pep), and IS(OGTT C-pep). These indexes were then correlated with insulin sensitivity estimated from the IS(OGTT). RESULTS The strongest correlation with the IS(OGTT) was obtained for IS(OGTT C-pep) (r = 0.792, P < 0.001). Further, the correlations of IS(HOMA) (C-pep) and IS(QUICKI C-pep) with IS(OGTT) were also significant (r = 0.676, P < 0.001 and r = 0.707, P < 0.001, respectively). CONCLUSIONS These data suggest that calculated IS(OGTT C-pep) is an excellent predictor of insulin sensitivity in pregnancy and can be used to estimate insulin sensitivity in over 25,000 women participating in the HAPO study.

Hormonal and metabolic factors associated with variations in insulin sensitivity in human pregnancy.

OBJECTIVE: The objective of this study was to determine maternal hormonal and metabolic factors associated with insulin sensitivity in human pregnancy. RESEARCH DESIGN AND METHODS: This was a prospective observational cross-sectional study of 180 normal pregnant women, using samples collected at the time of a blinded oral glucose tolerance test (OGTT) between 24 and 32 weeks' gestation as an ancillary to the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study. The study was conducted at two public university teaching hospitals, Cleveland, Ohio, and Brisbane, Australia. Fasting maternal serum cholesterol, triglycerides, free fatty acids, insulin, leptin, tumor necrosis factor-alpha, placental growth hormone (PGH), insulin-like growth factors (IGFs) 1 and 2, and insulin-like growth factor binding proteins (IGFBPs) 1 and 3 were assayed. Correlation and multiple regression analyses were used to determine factors associated with maternal insulin sensitivity (IS) estimated using both OGTT-derived (IS(OGTT)) and fasting (using the homeostasis model assessment [HOMA]; IS(HOMA)) insulin and glucose concentrations. RESULTS: Insulin sensitivity correlated (r = x and y for IS(OGTT) and IS(HOMA,) respectively) with fasting maternal serum leptin (-0.44 and -0.52), IGFBP1 (0.42 and 0.39), and triglycerides (-0.31 and -0.27). These factors were significantly associated with insulin sensitivity in multiple regression analyses (adjusted R(2) 0.44 for IS(OGTT) and IS(HOMA)). These variables explained more than 40% of the variance in estimates of insulin sensitivity. CONCLUSIONS: Maternal hormonal and metabolic factors related to the placenta, adipose tissue, and the growth hormone axis are associated with the variation in insulin sensitivity seen during normal human pregnancy.

Perinatal risk factors for childhood obesity and metabolic dysregulation.

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 +/- 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.

Body mass index: a true indicator of body fat in obese gravidas.

OBJECTIVE: To determine the relationship between body mass index (BMI) and percent body fat in overweight/obese pregnant women (BMI >25) before and during pregnancy. STUDY DESIGN: Thirteen overweight women were evaluated longitudinally (prospective cohort study design) before conception, in early gestation (12-22 weeks) and in late gestation (31-36 weeks). BMI was calculated as weight (kg)/height (m)2, and percent body fat was estimated using hydrodensitometry with correction for residual lung volume. RESULTS: The correlation between BMI and percent body fat before conception was r2 = 0.86 (p = 0.001). Furthermore, the correlation remained strong in early pregnancy, r2 = 0.84 (p = 0.001), but was less strong yet significant, r2 = 0.54 (p = 0.004), in late gestation. CONCLUSION: In overweight women, the correlation between BMI and percent body fat remained significant during pregnancy. However, the correlation weakened as the pregnancy advanced.

Increased neonatal fat mass, not lean body mass, is associated with maternal obesity.

OBJECTIVE: The purpose of this study was to compare body composition measures in neonates of women who were overweight/obese (body mass index, > or = 25 kg/m2) versus women who were lean/average (body mass index, < 25 kg/m2), all of whom had normal glucose tolerance levels. STUDY DESIGN: Seventy-six neonates (34 female and 42 male) of singleton pregnancies of pregravid overweight/obese women and 144 neonates (67 female and 77 male) of lean/average women were assessed with anthropometric measures and total body electrical conductivity evaluation of body composition at birth. RESULTS: There was a borderline increase in birthweight (3436 +/- 567 g vs 3284 +/- 534 g; P = .051) but not lean body mass (3020 +/- 410 g vs 2950 +/- 400 g; P = .23) in the overweight/obese versus lean/average weight groups. However, there were significant increases in percent body fat (11.6% +/- 4.7% vs 9.7 +/- 4.3%; P = .003) and fat mass (420 +/- 220 g vs 380 +/- 170 g; P = .01) in neonates of overweight/obese women versus lean/average weight women. CONCLUSION: Overweight/obese women with normal glucose tolerance levels have neonates who are heavier than lean/average weight women because of increased adiposity. We speculate that this increased obesity in offspring of obese women with normal glucose tolerance levels is a significant risk for adolescent obesity and components of the metabolic syndrome.

What proportion of birth weight is attributable to maternal glucose among infants of diabetic women?

OBJECTIVE: This study was undertaken to determine the proportion of birth weight attributable to glucose concentrations of diabetic mothers. STUDY DESIGN: Data of diabetic women who used insulin were eligible for analysis if the women had been treated during pregnancy for at least 12 weeks, and had recorded at least 50% of 4 daily glucose checks (fasting and 1-hour postprandial) until the last office visit before delivery. The independent association between maternal glucose values and demographics and birth weight percentiles for gestational age and gender were analyzed by multiple regression methods. RESULTS: Data of 90 diabetic women were analyzed. Only third-trimester glucose concentrations were associated with birth weight. Prepregnancy body mass index was also selected in the models, including second- and/or third-trimester glucose. Together, these variables explained 18% of the variance in birth weight percentiles. CONCLUSION: Maternal glycemia during third-trimester and prepregnancy body mass index are independent predictors of birth weight in pregnancies complicated by insulin-requiring gestational or type 2 diabetes.

Maternal interleukin-6: marker of fetal growth and adiposity.

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.

Evaluation of body composition of large-for-gestational-age infants of women with gestational diabetes mellitus compared with women with normal glucose tolerance levels.

OBJECTIVE: The purpose of this study was to determine whether there is a difference in body composition and the factors that are associated with fat mass in the large-for-gestational-age infants of women with gestational diabetes mellitus compared with the large-for-gestational-age infants of women with normal glucose tolerance levels. STUDY DESIGN: Large for gestational age was defined as weight >90th percentile for gestational age, race, and sex on the basis of our population's normative data. Anthropometric measurements and/or total body electrical conductivity estimated body composition that included fat mass, percent body fat, and lean body mass were obtained. Multiple stepwise regression was used to determine factors correlating with fat mass. RESULTS: Fifty cases of women with gestational diabetes mellitus and 52 cases of women with normal glucose tolerance levels were evaluated. Infants of mothers with gestational diabetes mellitus had increased fat mass (662 vs 563 g; P = .02) and percent body fat (16.2% vs 13.5%; P = .002) but decreased lean body mass (3400 vs 3557 g; P = .0009), as compared with infants of mothers with normal glucose tolerance levels, despite similar birth weights. Stepwise regression on all 102 women showed gestational age and a diagnosis of gestational diabetes mellitus correlated with fat mass (r2 = 0.11; P = .001). For gestational diabetes mellitus alone, both gestational age and fasting value of the oral glucose tolerance test correlated with fat mass and percent body fat (r2 = 0.33 [P = .0009] and r2 = 0.26 [P = .005], respectively). CONCLUSION: Large-for-gestational-age infants of mothers with gestational diabetes mellitus have increased fat mass and decreased lean body mass compared with infants of mothers with normal glucose tolerance levels. In gestational diabetes mellitus, gestational age and fasting value of the oral glucose tolerance test correlated best with fat mass.

Longitudinal changes in energy expenditure and body composition in obese women with normal and impaired glucose tolerance.

Our primary objective was to evaluate changes in energy expenditure and body composition in women with normal glucose tolerance (NGT) and gestational diabetes mellitus (GDM). A secondary objective was to examine the relationship between maternal leptin and nutrient metabolism. Fifteen obese women, eight with NGT and seven with GDM, were evaluated before conception (P), at 12-14 wk (E), and at 34-36 wk (L). Energy expenditure and glucose and fat metabolism were measured using indirect calorimetry. Basal hepatic glucose production was measured using [6,6-2H2]glucose and insulin sensitivity by euglycemic clamp. There was a significant increase (6.6 kg, P = 0.0001) in fat mass from P to L. There was a 30% (P = 0.0001) increase in basal O2 consumption (VO2, ml/min). There were no significant changes in carbohydrate oxidation during fasting or storage from P to L. There was, however, a significant (P = 0.0001) 150% increase in basal fat oxidation (mg/min) from P to L. Under hyperinsulinemic conditions, there were similar 25% increases in VO2 (P = 0.0001) from P to L in both groups. Because of the significant increases in insulin resistance from P to L, there was a significant (P = 0.0001) decrease in carbohydrate oxidation and storage. There was a net change from lipogenesis to lipolysis, i.e., fat oxidation (30-40 mg/min, P = 0.0001) from P to L. Serum leptin concentrations had a significant positive correlation with fat oxidation at E (r = 0.76, P = 0.005) and L (r = 0.72, P = 0.009). Pregnancy in obese women is associated with significant increases in fat mass and basal metabolic rate and an increased reliance on lipids both in the basal state and during the clamp. These modifications are similar in women with NGT and GDM. The increased reliance on fat metabolism is accompanied by a concomitant decrease in carbohydrate metabolism during hyperinsulinemia. The increase in fat oxidation may be related to increased maternal serum leptin.

The influence of obesity and gestational diabetes mellitus on accretion and the distribution of adipose tissue in pregnancy.

OBJECTIVE: The purpose of this study was to evaluate the effect of pregravid obesity and gestational diabetes mellitus (GDM) on the longitudinal accretion and distribution of adipose tissue in pregnancy. STUDY DESIGN: Women with normal glucose tolerance and GDM were evaluated before conception, early (12-14 weeks) and late (33-36 weeks) in gestation. Fat mass, lean body mass, and percent body fat were assessed longitudinally with hydrodensitometry. Serial biceps, triceps, subscapular, iliac, costal, mid thigh, and lower thigh skinfold measurements quantified the changes in fat mass distribution. Pregravid obesity was defined as >25% body fat. RESULTS: Subjects included 19 patients with GDM (5 lean women, 14 obese women), and 33 patients with normal glucose tolerance (controls; 12 lean women, 21 obese women). GDM and control subjects were similar in pregravid percent body fat (29.6% vs 27.9%, P=.47) and fat mass (20.8 kg vs 18.2 kg, P=.37). Values for subjects with GDM and controls were also similar in terms of percent body fat, fat mass, and weight gained (change in percent body fat, -0.7% vs 1.9% [P=.07]; change in fat mass, 3.8 kg vs 5.0 kg [P=.08]; change in weight, 12.0 kg vs 13.2 kg [P=.35]). Lean subjects gained more percent body fat compared with obese subjects (change in percent body fat, 3.3% vs 0.1% [P=.004]) but gained similar amounts of fat mass (change in fat mass, 4.7 kg vs 4.2 kg [P=.58]), lean body mass (7.6 kg vs 8.8 kg [P=.18]), and weight (change in weight, 12.3kg vs 13.0 kg [P=.61]) The distribution of adipose tissue that was accumulated as estimated with skinfold measurements was similar between patients with GDM and glucose tolerance (P>.05 for all changes in skinfolds), but significantly different between lean and obese patients (P<.05 for all changes in skinfolds). Lean women gained a predominance of adipose tissue peripherally over that in obese women. CONCLUSION: Lean women accrue significantly more fat mass than obese women, regardless of glucose tolerance. Pregestational obesity rather than GDM influences the distribution of adipose accretion.

Increased fetal adiposity: a very sensitive marker of abnormal in utero development.

OBJECTIVE: Because offspring of women with gestational diabetes mellitus have an increased risk of obesity and diabetes mellitus as young adults, our purpose was to characterize body composition at birth in infants of women with gestational diabetes mellitus and normal glucose tolerance. STUDY DESIGN: One hundred ninety-five infants of women with gestational diabetes mellitus and 220 infants of women with normal glucose tolerance had anthropometric measurements and total body electrical conductivity body composition evaluations at birth. Parental demographic, anthropometric, medical and family history data, and diagnostic glucose values were used to develop a stepwise regression model that related to fetal growth and body composition. RESULTS: There was no significant difference in birth weight (gestational diabetes mellitus [3398+/-550 g] vs normal glucose tolerance [3337+/-549 g], P=.26) or fat-free mass (gestational diabetes mellitus [2962+/-405 g] vs normal glucose tolerance [2975+/-408 g], P=.74) between groups. However, infants of women with gestational diabetes mellitus had significantly greater skinfold measures (P=.0001) and fat mass (gestational diabetes mellitus [436+/-206 g] vs normal glucose tolerance [362+/-198 g], P=.0002) compared with infants of women with normal glucose tolerance. In the gestational diabetes mellitus group, although gestational age had the strongest correlation with birth weight and fat-free mass, fasting glucose level had the strongest correlation with neonatal adiposity. CONCLUSION: Infants of women with gestational diabetes mellitus, even when they are average weight for gestational age, have increased body fat compared with infants of women with normal glucose tolerance. Maternal fasting glucose level was the strongest predictor of fat mass in infants of women with gestational diabetes mellitus. This increase in body fat may be a significant risk factor for obesity in early childhood and possibly in later life.

TNF-alpha is a predictor of insulin resistance in human pregnancy.

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.