Sugar-Sweetened Beverages and Risk of Metabolic Syndrome and Type 2 Diabetes: A meta-analysis

OBJECTIVE

Consumption of sugar-sweetened beverages (SSBs), which include soft drinks, fruit drinks, iced tea, and energy and vitamin water drinks has risen across the globe. Regular consumption of SSBs has been associated with weight gain and risk of overweight and obesity, but the role of SSBs in the development of related chronic metabolic diseases, such as metabolic syndrome and type 2 diabetes, has not been quantitatively reviewed.

RESEARCH DESIGN AND METHODS

We searched the MEDLINE database up to May 2010 for prospective cohort studies of SSB intake and risk of metabolic syndrome and type 2 diabetes. We identified 11 studies (three for metabolic syndrome and eight for type 2 diabetes) for inclusion in a random-effects meta-analysis comparing SSB intake in the highest to lowest quantiles in relation to risk of metabolic syndrome and type 2 diabetes.

RESULTS

Based on data from these studies, including 310,819 participants and 15,043 cases of type 2 diabetes, individuals in the highest quantile of SSB intake (most often 1–2 servings/day) had a 26% greater risk of developing type 2 diabetes than those in the lowest quantile (none or <1 serving/month) (relative risk [RR] 1.26 [95% CI 1.12–1.41]). Among studies evaluating metabolic syndrome, including 19,431 participants and 5,803 cases, the pooled RR was 1.20 [1.02–1.42].

CONCLUSIONS

In addition to weight gain, higher consumption of SSBs is associated with development of metabolic syndrome and type 2 diabetes. These data provide empirical evidence that intake of SSBs should be limited to reduce obesity-related risk of chronic metabolic diseases.In recent decades, consumption of sugar-sweetened beverages (SSBs), which include the full spectrum of soft drinks (soda), fruit drinks, and energy and vitamin water drinks has been steadily increasing to various degrees across the globe. For example, in the U.S. between the late 1970s and 2006 the per capita consumption of SSBs increased from 64.4 to 141.7 kcal/day, representing more than a twofold increase (1). Similar temporal patterns have been shown for Mexico, where currently >12% of total energy intake is contributed by these beverages (2). Of particular concern is the rapid trajectory of increase evident in many developing countries where access to SSBs has grown concomitantly with rising rates of urbanization. Sales figures from Coca Cola''s 2007 annual report show that during 2007, India and China experienced growths of 14 and 18%, respectively, in the volume of beverages sold, indicative of substantial increases in sales at the population level (3).SSBs, which are now the primary source of added sugars in the U.S. diet, are composed of energy-containing sweeteners such as sucrose, high-fructose corn syrup, or fruit juice concentrates, all of which have essentially similar metabolic effects (4). In contrast, a beverage that is 100% fruit juice and not blended with added sweeteners is not considered an SSB. Increasingly, groups of scholars and organizations such as the American Heart Association are calling for major reductions in consumption of SSBs (5,6). Findings from well-powered prospective epidemiological studies have shown consistent positive associations between SSB intake and weight gain and obesity in both children and adults (7). Emerging evidence also suggests that habitual SSB consumption is associated with increased risk of metabolic syndrome and type 2 diabetes (8). SSBs are thought to lead to weight gain by virtue of their high sugar content and incomplete compensation for total energy at subsequent meals after intake of liquid calories (7). Because of the high content of rapidly absorbable carbohydrates such as sucrose (50% glucose and 50% fructose) and high-fructose corn syrup (most often 45% glucose and 55% fructose), in conjunction with the large volumes consumed, SSBs may increase the risk of metabolic syndrome and type 2 diabetes not only through obesity but also by increasing dietary glycemic load, leading to insulin resistance, β-cell dysfunction, and inflammation (9). Additional metabolic effects of these beverages may also lead to hypertension and promote accumulation of visceral adipose tissue and of ectopic fat due to elevated hepatic de novo lipogenesis (10), resulting in the development of high triglycerides and low HDL cholesterol and small, dense LDL, although the specific metabolic effects of fructose versus glucose remain to be further examined. To summarize the available literature, we conducted a meta-analysis of prospective cohort studies to examine the relationship between SSB consumption and risk of developing metabolic syndrome and type 2 diabetes.     

Consumption of sugar-sweetened beverages among adults with type 2 diabetes

OBJECTIVE

To examine patterns of sugar-sweetened beverage (SSB) consumption among U.S. adults with type 2 diabetes in 2003–2006.

RESEARCH DESIGN AND METHODS

We analyzed 24-h dietary recall data from the National Health and Nutrition Examination Survey 2003–2006 to estimate SSB consumption levels among 1,090 adults (aged ≥20 years) with type 2 diabetes overall and by diagnosis and control status of their diabetes.

RESULTS

In 2003–2006, 45% of adults with diabetes consumed SSBs on a given day, obtaining an average of 202 calories and 47 g of sugar. Undiagnosed adults with diabetes were significantly more likely to consume SSBs than diagnosed adults (60 vs. 38% diagnosed/uncontrolled [P < 0.001] and 43% diagnosed/controlled [P = 0.001]) and were less likely to consume diet beverages (18 vs. 50% diagnosed/uncontrolled [P < 0.001] and 40% diagnosed/controlled [P < 0.001]). Men consumed significantly more SSBs than women (P = 0.027), younger adults (aged 20–44) more than older adults (45–64 and ≥65; P < 0.001), non–Hispanic black more than whites (P = 0.010); and low-income individuals (quartile 1) more than higher-income individuals (quartile 3, P = 0.040; quartile 4, P = 0.013). For most demographic and body weight categories, adults who were undiagnosed consumed more sugar from SSBs than adults who were diagnosed.

CONCLUSIONS

SSB consumption is high among adults with diabetes, particularly among those who are undiagnosed.Consumption of sugar-sweetened beverages (SSBs) has been linked to higher incidence of type 2 diabetes (1,2), which affects 10% of adults or 23.5 million Americans (3). The economic burden of diabetes is estimated to be $174 billion annually in direct and indirect costs (4). Of particular concern are minority and low socioeconomic status individuals, who are disproportionately affected by diabetes (5). The American Cancer Society, the American Diabetes Association, and the American Heart Association recommend that individuals with diabetes limit their intake of beverages with added sugar (6). The American Heart Association recommends that women consume no more than 25 g (∼100 kcal) and men no more than 37.5 g (∼150 kcal) per day of added sugar (7).Although an extensive body of research has examined trends and patterns of SSB consumption and shows that consumption increased considerably for children (8) and adults (9) during the period 1988–1994 to 1999–2004—from 242 to 271 kcal/day among children and from 157 to 203 kcal/day among adults—no known studies have focused on individuals with diabetes. Replacing SSBs with noncaloric beverages can offer a relatively simple, low-cost option to improve glycemic control and help individuals with diabetes to achieve or maintain a healthy weight (10). Identifying variations in SSB consumption by subpopulation groups is also useful for the development of targeted policies or nutrition programs, or both.The purpose of this study was to describe national patterns in the percentage of SSB drinkers and the consumption levels among U.S. adults with diabetes. In addition to overall consumption, we also investigated differences by whether their diabetes status was diagnosed and well controlled and by demographic characteristics and body weight category.     

The Relative Contribution of Prepregnancy Overweight and Obesity,Gestational Weight Gain,and IADPSG-Defined Gestational Diabetes Mellitus to Fetal Overgrowth

OBJECTIVE

The International Association of Diabetes in Pregnancy Study Groups (IADPSG) criteria for diagnosis of gestational diabetes mellitus (GDM) identifies women and infants at risk for adverse outcomes, which are also strongly associated with maternal overweight, obesity, and excess gestational weight gain.

RESEARCH DESIGN AND METHODS

We conducted a retrospective study of 9,835 women who delivered at ≥20 weeks’ gestation; had a prenatal, 2-h, 75-g oral glucose tolerance test; and were not treated with diet, exercise, or antidiabetic medications during pregnancy. Women were classified as having GDM based on IADPSG criteria and were categorized into six mutually exclusive prepregnancy BMI/GDM groups: normal weight ± GDM, overweight ± GDM, and obese ± GDM.

RESULTS

Overall, 5,851 (59.5%) women were overweight or obese and 1,892 (19.2%) had GDM. Of those with GDM, 1,443 (76.3%) were overweight or obese. The prevalence of large-for-gestational-age (LGA) infants was significantly higher for overweight and obese women without GDM compared with their normal-weight counterparts. Among women without GDM, 21.6% of LGA infants were attributable to maternal overweight and obesity, and the combination of being overweight or obese and having GDM accounted for 23.3% of LGA infants. Increasing gestational weight gain was associated with a higher prevalence of LGA in all groups.

CONCLUSIONS

Prepregnancy overweight and obesity account for a high proportion of LGA, even in the absence of GDM. Interventions that focus on maternal overweight/obesity and gestational weight gain, regardless of GDM status, have the potential to reach far more women at risk for having an LGA infant.Both International Association of Diabetes in Pregnancy Study Groups (IADPSG)–defined gestational diabetes mellitus (GDM) (1,2) and maternal overweight and obesity (2–4) are associated with increased risk for adverse maternal and perinatal outcomes, such as fetal overgrowth, shoulder dystocia and birth injury, pre-eclampsia, and preterm delivery. Although most studies addressing the effects of maternal BMI on adverse outcomes include women with GDM (2–6), a few have reported these associations in overweight or obese women with normal glucose tolerance (7–9). Scant data exist that demonstrate associations between GDM and adverse outcomes in the absence of overweight or obesity (9).Although it is currently estimated that 10–25% of pregnant women develop GDM by IADPSG criteria (1,2,10), 50–60% of women are overweight or obese at the start of their pregnancies (6,7,11,12). Prepregnancy overweight and obesity are also associated with GDM development, as 65–75% of women with GDM are also overweight or obese (11,13). As such, the relative impact of prepregnancy BMI and maternal glycemia during pregnancy on adverse maternal and perinatal outcomes is difficult to tease apart. Moreover, excess gestational weight gain complicates a large number of pregnancies and is highly correlated with maternal overweight and obesity, as well as the development of GDM (14–16). Despite the fact that studies have reported increases in the risk of adverse outcomes with increasing gestational weight gain (13,15–18), many studies examining the effects of maternal obesity and/or glucose levels have not accounted for this important factor.The purpose of this study was to examine the effects of prepregnancy overweight and obesity among women with and without IADPSG-defined GDM on clinically important adverse outcomes, focusing primarily on fetal overgrowth, one of the most prevalent adverse conditions associated with maternal and neonatal morbidity. In addition to magnitude of association, we determine the proportion of large-for-gestational-age (LGA) infants attributable to each risk factor and combinations thereof. We also examine the relative contribution of increasing gestational weight gain to the development of LGA.     

Diabetes-Related Behaviors in Latinas and Non-Latinas in California

OBJECTIVE

Certain dietary and physical activity behaviors have been associated with the risk of developing type 2 diabetes, yet little is known about the prevalence of these behaviors among Latinas (Latino women). The purpose of this cross-sectional study was to compare the prevalence of diabetes-related behaviors in Latinas and non-Latinas.

RESEARCH DESIGN AND METHODS

Using data from the 2009 California Health Interview Survey, we compared self-reported diabetes-related behaviors of Latinas (n = 4,321) to non-Latinas (n = 21,112) after excluding women who were pregnant or had diabetes. For six behaviors, we determined the cut point for the least healthy tertile: walking, doing moderate to vigorous physical activity, and consuming fried potatoes, sugar-sweetened beverages (SSBs), desserts, and fast food. We used logistic regression to examine the association between Latina ethnicity and being in the least healthy tertile compared with the other two tertiles for each of these behaviors.

RESULTS

In multivariate models adjusted for age, income, education, marital status, health status, smoking, and acculturation, Latinas had a higher risk (odds ratio [95% CI]) of being in the least healthy tertile for the consumption of fast food (1.94 [1.63–2.31]), SSBs (1.53 [1.29–1.82]), and fried potatoes (1.32 [1.18–1.67]), and lower risk for desserts (0.82 [0.70–0.95]). Latinas and non-Latinas had similar physical activity levels.

CONCLUSIONS

Dietary differences between Latinas and non-Latinas (particularly in the consumption of fast food and SSBs) may be the focus of interventions to prevent diabetes in Latinas. Further research among Latinas is needed to understand and modify these dietary behaviors.Type 2 diabetes results in a tremendous public health and economic burden, affecting almost 12% of the U.S. adult population (1) and costing ∼$218 billion annually (2). The diabetes epidemic in the U.S. disproportionately affects Latinos, with the prevalence in Mexican-American adults being twice that of whites (3). The incidence and prevalence of diabetes continue to rise (4) along with the size of the Latino population, suggesting that the burden of diabetes on the U.S. health care system will increase in the future. In addition, high rates of overweight and obesity in Latinos confer an increased risk of diabetes in this growing population (5). Compared with all other demographic groups, Latinas (Latino women) have the highest lifetime risk of developing diabetes, estimated at 53% (6). Reducing the burden of diabetes in the U.S. requires a better understanding of the factors underlying Latinas’ high risk for developing this disease.Numerous epidemiologic studies have identified specific dietary and physical activity behaviors that impact diabetes risk. Dietary risk factors include the consumption of fried potatoes (7), fast food (8), sugar-sweetened beverages (SSBs) (9), and desserts (10). Both observational (11) and experimental studies (12) suggest that physical activity helps prevent diabetes. Many studies have examined the prevalence of these diabetes-related behaviors across racial and ethnic groups (13–24). However, almost none of this research involving Latinos analyzes data separately for Latino women, even though their lifetime risk of diabetes is almost 20% higher than Latino men (6). Data on the prevalence of diabetes-related behaviors in Latinas might improve diabetes prevention efforts in this population. Highly effective lifestyle programs to prevent diabetes by focusing on diet and physical activity already exist and have been studied in diverse populations (25).Using a population-based sample from California (a state with ∼7 million Latinas) (26), we examined differences between Latinas and non-Latinas in the prevalence of six diabetes-related behaviors: walking, moderate to vigorous physical activity (MVPA), and consumption of fried potatoes, SSBs, desserts, and fast food. To make our findings useful to clinicians seeking to tailor diabetes prevention messages to Latinas, we compared this group to non-Latinas. Based on our literature review, we hypothesized that Latina ethnicity would be associated with less healthy dietary and physical activity behaviors, compared with non-Latina ethnicity.     

Early Prediction of Gestational Diabetes Mellitus in Vietnam: Clinical impact of currently recommended diagnostic criteria

OBJECTIVE

We aimed to compare the discriminative power of prognostic models for early prediction of women at risk for the development of gestational diabetes mellitus (GDM) using four currently recommended diagnostic criteria based on the 75-g oral glucose tolerance test (OGTT). We also described the potential effect of application of the models into clinical practice.

RESEARCH DESIGN AND METHODS

A prospective cross-sectional study of 2,772 pregnant women was conducted at a referral maternity center in Vietnam. GDM was determined by the American Diabetes Association (ADA), International Association of the Diabetes and Pregnancy Study Groups (IADPSG), Australasian Diabetes in Pregnancy Society (ADIPS), and World Health Organization (WHO) criteria. Prognostic models were developed using the Bayesian model averaging approach, and discriminative power was assessed by area under the curve. Different thresholds of predicted risk of developing GDM were applied to describe the clinical impact of the diagnostic criteria.

RESULTS

The magnitude of GDM varied substantially by the diagnostic criteria: 5.9% (ADA), 20.4% (IADPSG), 20.8% (ADIPS), and 24.3% (WHO). The ADA prognostic model, consisting of age and BMI at booking, had the best discriminative power (area under the curve of 0.71) and the most favorable cost-effective ratio if implemented in clinical practice. Selective screening of women for GDM using the ADA model with a risk threshold of 3% gave 93% sensitivity for identification of women with GDM with a 27% reduction in the number of OGTTs required.

CONCLUSIONS

A simple prognostic model using age and BMI at booking could be used for selective screening of GDM in Vietnam and in other low- and middle-income settings.Gestational diabetes mellitus (GDM) has increased worldwide (1) and occurs in 1–28% of all pregnancies (2). This figure varies substantially between populations and the diagnostic criteria used. GDM is associated with adverse perinatal outcomes (3), future development of type 2 diabetes in the mother (4), and an increased risk of the offspring developing obesity and impaired glucose tolerance in childhood and early adulthood (5,6). Despite the recent publication of screening guidelines based on perinatal outcomes from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) multinational large study, no international consensus for the screening of GDM has been reached (2).The 75-g oral glucose tolerance test (OGTT) is accepted as the method of screening for GDM by the American Diabetes Association (ADA) (7), the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) (8), World Health Organization (WHO) (9), and Australasian Diabetes in Pregnancy Society (ADIPS) (10). There has long been a debate about whether selective or universal screening for GDM should be performed. A universal approach to screening detects more women with GDM but requires greater resources (11,12). In low- and middle-income countries, universal screening poses particular challenges. High prevalence and limited resources available for management and health promotion may render universal screening impossible in under-resourced settings. Under these circumstances, a selective approach may be a reasonable alternative (13,14). Selective screening in women at high-risk for GDM can also result in a substantial decrease in the number of OGTTs performed compared with a universal screening, with acceptable sensitivity in case detection (14,15). Importantly, improved performance with a selective approach has been reported if the risk indicators are derived from the population where screening is being carried out (13–15). Unfortunately, which selective screening approach has the most favorable cost-effective profile if implemented in daily clinical practice has yet to be determined. These data are crucial in low- and middle-income countries where health care centers are overcrowded, understaffed, and insufficiently resourced.This study aims to determine the sensitivity and specificity of prognostic models for the selective screening of GDM in a low-resource setting. We compare four major diagnostic criteria that use the 75-g OGTT at 28 weeks’ gestation for diagnosis of GDM. We report the ability of different predictive models to identify GDM cases and the potential for reduction in the number of OGTTs needed. Using this information, we aim to determine the optimum selective screening model and diagnostic criteria for this setting.     

Determinants of body fat in infants of women with gestational diabetes mellitus differ with fetal sex

OBJECTIVE

Neonatal adiposity is a well-recognized complication of gestational diabetes mellitus (GDM). This study aimed to identify factors influencing adiposity in male and female infants of women treated for GDM.

RESEARCH DESIGN AND METHODS

This was a prospective study of 84 women with GDM. Daily blood glucose levels (BGLs) were retrieved from glucose meters, and overall mean fasting and mean 2-h postprandial BGLs were calculated for each woman. Infant body composition was measured at birth, and regression analysis was used to identify significant predictors of infant body fat separately in male and female infants.

RESULTS

Maternal fasting BGL was the major predictor of adiposity in male infants but had little relationship to adiposity in female infants. In male infants, percent fat was increased by 0.44% for each 0.1 mmol/L increase in mean maternal fasting BGL. Maternal BMI was the primary predictor in female infants but had little effect in males. In female infants, percent fat was increased by 0.11% for each 1 kg/m² increase in maternal prepregnancy BMI.

CONCLUSIONS

Fetal sex may influence the impact that treatment strategies for GDM have on infant adiposity.The maternal metabolic disturbance of gestational diabetes mellitus (GDM) affects fetal development and alters birth weight, BMI, and percent body fat at birth (1,2). Current treatment of GDM achieves normalization of birth weight and reduces neonatal complications (3). However, the effects of GDM on the offspring extend well beyond the fetal period and, thus, offspring of women with GDM also have an increased risk of unfavorable long-term outcomes such as obesity and diabetes, well above that explained by genetics alone (4), even after treatment.To date, studies designed to inform optimal treatment of GDM have focused on normalization of birth weight, but neonatal adiposity may be a more sensitive marker of disturbed in utero metabolism, risk of obesity, and poor long-term health than birth weight alone (1). Body fat at birth is elevated in infants born to women with GDM even when birth weight is normal (1). In a group of 6- to 12-year-old children born to women with GDM, percent body fat in childhood was significantly correlated to body fat at birth, but there was no relationship between birth weight and weight at the time of study (5). Even though treatment of mild GDM does reduce the incidence of macrosomia, it does not reduce the incidence of obesity in the offspring at 4–5 years (6).To interrupt the obesity cycle and reduce the risk of future poor adult health, it may be necessary to normalize neonatal adiposity as well as birth weight. To do this, it is essential to understand the factors that determine adiposity in infants of women with GDM.While genetic factors may be the primary determinant of lean body mass, fetal fat mass may be more strongly influenced by the in utero environment (7). A range of maternal factors have been identified as determinants of neonatal size and body fat, including maternal BMI, parity, maternal glucose concentration, and insulin sensitivity (8–10). Higher gestational weight gain is associated with increased infant birth weight in lean and moderately overweight women (11) and in women with normal glucose tolerance (9) but not in obese women (11) or women with GDM (9). However, the factors influencing fetal fat accretion remain poorly understood.Both body weight and body composition at birth are different in male and female infants (12), and sex of the infant has been reported as a significant determinant of each (9). We hypothesized that the determinants of fetal body composition may also differ with fetal sex. The aim of this study was to identify factors that influence adiposity in male and female infants born to women treated for GDM.     

Sleep-Disordered Breathing and Gestational Diabetes Mellitus: A meta-analysis of 9,795 participants enrolled in epidemiological observational studies

OBJECTIVE

Recently, sleep-disordered breathing (SDB) has been reported to be associated with the development of gestational diabetes mellitus (GDM). Accordingly, as this is emergent area of research that has significant clinical relevance, the objective of this meta-analysis is to examine the relationship between SDB with GDM.

RESEARCH DESIGN AND METHODS

We searched several electronic databases for all of the studies published before January 2013 and reviewed references of published articles. Meta-analytic procedures were used to estimate the unadjusted and BMI-adjusted odds ratios (ORs) using a random effects model. Significant values, weighted effect sizes, and 95% CIs were calculated, and tests of homogeneity of variance were performed.

RESULTS

Results from nine independent studies with a total of 9,795 pregnant women showed that SDB was significantly associated with an increased risk of GDM. Women with SDB had a more than threefold increased risk of GDM, with a pooled BMI-adjusted OR 3.06 (95% CI 1.89–4.96).

CONCLUSIONS

These findings demonstrate a significant association between SDB and GDM that is evident even after considered confounding by obesity. This meta-analysis indicates a need to evaluate the role of early recognition and treatment of SDB early during pregnancy.Gestational diabetes mellitus (GDM) is defined as carbohydrate intolerance of variable severity with onset or first recognition during pregnancy and often diagnosed at 24–28 weeks of gestation (1–3). GDM is a major concern for public health, as the number of affected women is expected to rise as a result of increased sedentary habits and hypercaloric diets (4).The impact of GDM on maternal and fetal health is well established. The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study showed that globally, GDM is associated with adverse perinatal and maternal outcomes such as fetal macrosomia, preeclampsia, primary cesarean section, neonatal hypoglycemia, premature delivery, intensive neonatal care, and hyperbilirubinemia, as well as with increased levels of cord blood serum C-peptide (5–8). The HAPO study also demonstrated that associations between maternal glycemia and adverse outcomes are continuous across the range of glucose concentrations and are observable even below diagnostic levels of diabetes (9). This broad range of morbidity indicates a need to identify modifiable risk factors for impaired glucose tolerance in pregnancy.Sleep-disordered breathing (SDB) has emerged as an important risk factor for the development of high blood pressure, heart failure, stroke, diabetes, atrial fibrillation, and premature mortality (10–12). The risk is particularly elevated among racial/ethnic minority groups and individuals from disadvantaged neighborhoods. Mounting evidence, from observational and experimental intervention studies, indicates that sleep disturbances, such as SDB (defined as habitual snoring or sleep study–documented obstructive sleep apnea), are associated with poor glucose control and possibly GDM (13,14).Experimental studies have shown that short sleep duration decreases insulin sensitivity compared with longer sleep (15,16). Experimental overnight intermittent hypoxemia, an essential feature of SDB, also alters glucose metabolism in animal and human studies (17,18). Epidemiological studies have shown that SDB is a risk factor for prevalent and incident diabetes, and recent clinical trials indicate that metabolic abnormalities improve with treatment of SDB (19,20).Recently, SDB has been reported to be associated with the development of GDM (21). This finding, if confirmed across populations, has a potential large public health impact related to the increasing prevalence of obesity, a major risk factor for SDB. The objective of this meta-analysis is to examine whether SDB is associated with the occurrence of GDM and to assess the extent to which such an association is influenced by control for prepregnancy or early pregnancy BMI.     

First-Trimester Follistatin-Like-3 Levels in Pregnancies Complicated by Subsequent Gestational Diabetes Mellitus

OBJECTIVE

To determine whether maternal levels of follistatin-like-3 (FSTL3), an inhibitor of activin and myostatin involved in glucose homeostasis, are altered in the first trimester of pregnancies complicated by subsequent gestational diabetes mellitus (GDM).

RESEARCH DESIGN AND METHODS

This was a nested case-control study of subjects enrolled in a prospective cohort of pregnant women with and without GDM (≥2 abnormal values on a 100-g glucose tolerance test at ∼28 weeks of gestation). We measured FSTL3 levels in serum collected during the first trimester of pregnancy. Logistic regression analyses were used to determine the risk of GDM.

RESULTS

Women who developed GDM (n = 37) had lower first-trimester serum levels of FSTL3 compared with women who did not (n = 127) (median 10,789 [interquartile range 7,013–18,939] vs. 30,670 [18,370–55,484] pg/ml, P < 0.001). When subjects were divided into tertiles based on FSTL3 levels, women with the lowest levels demonstrated a marked increase in risk for developing GDM in univariate (odds ratio 11.2 [95% CI 3.6–35.3]) and multivariate (14.0 [4.1–47.9]) analyses. There was a significant negative correlation between first-trimester FSTL3 levels and ∼28-week nonfasting glucose levels (r = −0.30, P < 0.001).

CONCLUSIONS

First-trimester FSTL3 levels are associated with glucose intolerance and GDM later in pregnancy.Gestational diabetes mellitus (GDM) afflicts 4% of pregnancies in the U.S. and is associated with unfavorable perinatal outcomes (1). Although GDM is characterized by glucose intolerance, β-cell dysfunction, and insulin resistance (1–3), the pathogenesis of GDM is not well understood. The association between GDM and insulin resistance postpartum and subsequent type 2 diabetes in up to 70% of mothers (1–4) has led to the theory that GDM is simply the unmasking of a chronic condition. However, GDM resolves, at least temporarily, with the delivery of the infant and placenta, occurs more often in twin pregnancy (5), and recurs only in 30–50% of subsequent pregnancies (6), suggesting that circulating factors released by the placenta may be involved, at least partially, in its pathogenesis.Pregnant women are typically screened for GDM at 24–28 weeks of gestation. Despite the fact that insulin sensitivity increases in the first trimester of pregnancy, a recent study showed that higher first-trimester levels of fasting blood glucose were linearly associated with increased risk of GDM, cesarean section, and macrosomia (7), suggesting that the pathophysiologic process that leads to GDM is underway weeks to months before its diagnosis. Thus, it is possible that factors linked with the pathogenesis of this condition may be present in blood samples well before the clinical diagnosis of GDM. Treatment of GDM in late pregnancy improves some adverse perinatal outcomes (8,9), but earlier detection of GDM through biomarker measurement in the first trimester of pregnancy may permit more time for intervention and lead to greater positive effects of treatment on maternal and fetal outcomes.Follistatin-like-3 (FSTL3, also referred to as FLRG), a follistatin homolog that inhibits circulating members of the transforming growth factor-β subfamily of proteins (10), is highly expressed by the placenta (11). FSTL3 expression is increased in placentas from pregnancies complicated by intrauterine growth restriction (12). Outside of pregnancy, FSTL3 may play a major role in glucose homeostasis, as FSTL3-null mice are characterized by pancreatic β-cell hyperplasia, elevated insulin levels, increased glucose tolerance, and upregulation of hepatic gluconeogenesis (13). Further evidence supporting a role for FSTL3 in glucose homeostasis includes the biological activities of activin A and myostatin, which are antagonized by FSTL3. Activin A promotes proliferation of β-cells and secretion of insulin (14,15); activin A levels were found to be elevated in pregnancies affected by GDM in previous studies (16,17). In mouse models, the absence of myostatin promotes insulin sensitivity and protects against weight gain (18,19). Although circulating levels of myostatin during pregnancy have not been described, myostatin is expressed by the human placenta and was shown to increase glucose uptake by placental explants (20).Based on the connection of FSTL3 to glucose homeostasis and the presence of insulin resistance and β-cell dysfunction in GDM, as well as the high expression levels of FSTL3 in the placentas of infants with small-for-gestational-age fetuses (12) and the occurrence of large-for-gestational-age infants in GDM, we hypothesized that circulating levels of FSTL3 would be altered in pregnancies complicated by GDM.     

Prepregnancy Dietary Protein Intake,Major Dietary Protein Sources,and the Risk of Gestational Diabetes Mellitus: A prospective cohort study

OBJECTIVE

Dietary protein is an important modulator of glucose metabolism. However, studies regarding the association between dietary protein intake and gestational diabetes mellitus (GDM) risk are sparse. This study was to examine the association.

RESEARCH DESIGN AND METHODS

Our study included 21,457 singleton pregnancies reported among 15,294 participants of the Nurses'' Health Study II cohort between 1991 and 2001. Included pregnancies were free of chronic diseases before pregnancy or previous GDM. Generalized estimating equations were used to estimate the relative risks (RRs) and 95% CIs.

RESULTS

After adjustment for age, parity, nondietary and dietary factors, and BMI, multivariable RRs (95% CIs) comparing the highest with lowest quintiles were 1.49 (1.03–2.17) for animal protein intake and 0.69 (0.50–0.97) for vegetable protein intake. The substitution of 5% energy from vegetable protein for animal protein was associated with a 51% lower risk of GDM (RR [95% CI], 0.49 [0.29–0.84]). For major dietary protein sources, multivariable RRs (95% CIs) comparing the highest with the lowest quintiles were 2.05 (1.55–2.73) for total red meat and 0.73 (0.56–0.95) for nuts, respectively. The substitution of red meat with poultry, fish, nuts, or legumes showed a significantly lower risk of GDM.

CONCLUSIONS

Higher intake of animal protein, in particular red meat, was significantly associated with a greater risk of GDM. By contrast, higher intake of vegetable protein, specifically nuts, was associated with a significantly lower risk. Substitution of vegetable protein for animal protein, as well as substitution of some healthy protein sources for red meat, was associated with a lower risk of GDM.Gestational diabetes mellitus (GDM), defined as glucose intolerance with onset or first recognition during pregnancy, is a growing health concern (1). Approximately 7% (ranging from 1 to 14%) of all pregnancies in the U.S. are complicated by GDM, resulting in more than 200,000 cases annually (2). GDM is associated with an increased risk of adverse pregnancy and perinatal outcomes (3) and long-term adverse health consequences for both mothers and their children, including a predisposition to obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM) (1,2,4); thus, the identification of modifiable risk factors that may contribute to the prevention of GDM is important.Recently, several dietary and lifestyle factors have been associated with GDM risk, although precise underlying mechanisms have yet to be established (5). Macronutrients including carbohydrates (6) and fats (7) have previously been evaluated for their association with GDM risk. The association with protein, however, remains unclear. Dietary proteins and amino acids are important modulators of glucose metabolism, and a diet high in protein may impact glucose homeostasis by promoting insulin resistance and increasing gluconeogenesis (8). Moreover, emerging data suggest that protein actions may vary by the amino acid types and food sources. For instance, a prospective cohort study in Europeans showed that long-term high intake of animal protein but not vegetable protein was associated with an increased risk of T2DM (9). Additionally, a study of metabolomics recently demonstrated that plasma concentrations of several kinds of amino acids, including branched-chain amino acids (BCAAs) and aromatic amino acids, were strongly and significantly associated with incident T2DM risk (10).Several major food sources of animal protein, such as red meat, were positively associated with the risk of both T2DM (11) and GDM (12). Conversely, higher intakes of nuts (13) and legumes (14) were associated with a lower risk of T2DM, but their associations with GDM have not yet been evaluated. In addition, the associations between other major sources of animal protein (e.g., poultry, fish, and dairy products) and GDM risk have not been reported.In this prospective cohort study, we aimed to examine the associations of prepregnancy dietary protein intake (total, animal, and vegetable protein) as well as major dietary protein sources with the risk of GDM. We also estimated the effect of substituting prepregnancy protein for carbohydrates, substituting vegetable protein for animal protein, and substituting other major dietary protein sources for red meat on the risk of GDM.     

Fetal Exposure to Altered Amniotic Fluid Glucose, Insulin, and Insulin-Like Growth Factor�CBinding Protein 1 Occurs Before Screening for Gestational Diabetes Mellitus

OBJECTIVE

We explored the possibility that perturbations in amniotic fluid glucose, insulin, and insulin-like growth factor–binding protein 1(IGFBP1) and/or metabolic acids exist before routine screening for GDM.

RESEARCH DESIGN AND METHODS

We selected consenting mother-infant pairs (n = 408) who met our inclusion criteria (singleton pregnancy, no genetic abnormalities, and no preexisting diabetes) and for whom sufficient amniotic fluid and appropriate medical information were available. We compared birth outcomes and second trimester amniotic fluid glucose, insulin, IGFBP1 concentrations, and amniotic fluid lactic, β-hydroxybutyric, and uric acids of mothers with gestational diabetes mellitus (GDM) (n = 52) with those of mothers with no diagnosis of GDM at >24 weeks (n = 356).

RESULTS

Higher amniotic fluid glucose, lactic acid, uric acid, and insulin and lower IGFBP1 concentrations were present by 15.1 ± 0.1 weeks in mothers in whom GDM was subsequently diagnosed. However, logistic regression showed that second trimester amniotic fluid glucose, but not insulin, IGFBP1, or metabolic acids was associated with an increased odds ratio (1.2 [95% CI 1.052–1.338]) for diagnosis of GDM at 24–28 weeks. In addition, probability contour maps that accounted for nonlinear relationships among the dynamically changing amniotic fluid constituents showed an increased risk for GDM with elevated second trimester amniotic fluid glucose in combination with either elevated amniotic fluid insulin or low amniotic fluid IGFBP1

CONCLUSIONS

Fetuses are exposed to increased amniotic fluid glucose before 15 weeks of gestation, suggesting that metabolic perturbations are underway before diagnosis and that earlier screening and intervention may be warranted.Gestational diabetes mellitus (GDM) is defined as a state of hyperglycemia arising during gestation that leads to increased glucose delivery to the developing fetus. Glucose is considered to be the principal metabolic fuel and supplies 50–80% of fetal glucose needs (1) with amniotic fluid supplying another 10–15% via fetal swallowing (2). Reportedly, amniotic fluid glucose concentrations are higher in mothers with type 1 or type 2 diabetes than in those without diabetes (3) and in those with GDM than in those without GDM (4). Amniotic fluid insulin is also elevated in mothers with GDM versus those without GDM (4–6). Some have suggested that amniotic fluid insulin may be a more sensitive early predictor of GDM than amniotic fluid glucose, but neither has emerged as an early screening tool (4). More recently, perturbations in insulin-like growth factors and their binding proteins have been implicated in diabetic pregnancies (7). In particular, lower concentrations of insulin-like growth factor–binding protein 1 (IGFBP1) in maternal plasma during the second trimester before diagnosis of GDM (8) and an inverse relationship with cord blood IGFBP1 of mothers with GDM at term and birth weight (9) have been described.It is well known that GDM is associated with poor perinatal outcomes, with macrosomia, and with a higher prevalence of diabetes in the offspring of mothers with GDM (10,11), but how soon during development these fetal insults begin is not clear. Two recent studies have linked subsequent diagnosis of GDM with irreversible oxidative damage to amniotic fluid albumin (12) and to lacticacidemia and fetal hypoxia in cord blood at term even in mothers with well-controlled GDM (13). Mothers with GDM also show evidence of altered ketogenesis and higher circulating concentrations of β-hydroxybutyrate that may be linked to increased gluconeogenesis and not to β-oxidation (14) and to increased uric acid (15) that could be related to hypoxia that often occurs with diabetes.GDM is usually diagnosed between 24 and 28 weeks of gestation by an oral glucose tolerance test (OGTT) (16). In this study, we explore the possibility that early fetal exposure to perturbations in second trimester amniotic fluid glucose, insulin, and IGFBP 1 and/or amniotic fluid lactic, β-hydroxybutyric, and uric acids may exist before current routine screening for GDM.     

Gestational diabetes mellitus in relation to maternal dietary heme iron and nonheme iron intake

OBJECTIVE

Higher heme iron intake is associated with increased type 2 diabetes risk. However, no previous study has evaluated gestational diabetes mellitus (GDM) risk in relation to heme iron intake during pregnancy. We investigated associations of maternal preconceptional and early pregnancy heme and nonheme iron intake with subsequent GDM risk.

RESEARCH DESIGN AND METHODS

We conducted a prospective cohort study of 3,158 pregnant women. A food frequency questionnaire was used to assess maternal diet. Multivariable generalized linear regression models were used to derive estimates of relative risks (RRs) and 95% CIs.

RESULTS

Approximately 5.0% of the cohort developed GDM (n = 158). Heme iron intake was positively and significantly associated with GDM risk (P_trend = 0.04). After adjusting for confounders, women reporting the highest heme iron intake levels (≥1.52 vs. <0.48 mg per day) experienced a 3.31-fold–increased GDM risk (95% CI 1.02–10.72). In fully adjusted models, we noted that a 1-mg per day increase in heme iron was associated with a 51% increased GDM risk (RR 1.51 [95% CI 0.99–2.36]). Nonheme iron was inversely, though not statistically significantly, associated with GDM risk, and the corresponding RRs were 1.00, 0.83, 0.62, and 0.61 across quartiles of nonheme iron intake (P_trend = 0.08).

CONCLUSIONS

High levels of dietary heme iron intake during the preconceptional and early pregnancy period may be associated with increased GDM risk. Associations of GDM risk with dietary nonheme iron intake are less clear. Confirmation of these findings by future studies is warranted.Iron deficiency is the most common nutritional deficiency in the U.S. and worldwide (1). In recent years, concerns about iron overload in developed countries have spurred research designed to assess cardiometabolic risks secondary to excess body iron stores and high dietary iron intake (2,3). As a result, iron now is viewed as a double-edged sword for living systems. Increasingly, clinical and epidemiological evidence suggest that both iron deficiency and iron overload influence the production of reactive oxygen species, leading to oxidative stress, systemic inflammation, and alternations in mitochondrial function (4). Taken together, cellular and metabolic alterations secondary to iron overload are thought to contribute to increased risks of hypertension (2), cardiovascular disease (5), and type 2 diabetes (3,6–8).The two kinds of dietary iron, heme and nonheme iron, with distinct metabolic pathways and intestinal absorption potential, are thought to play distinct roles in the pathophysiology of cardiometabolic disorders (4). Heme iron is exclusively present in hemoglobin and myoglobin from animal sources, including red meat and poultry. Nonheme iron, which is abundant in cereals, vegetables, fruits, beans, and dairy products, accounts for >85% of dietary iron intake. Although heme iron accounts for a smaller proportion of dietary iron, it is absorbed two to three times more readily than nonheme iron and is less affected by other dietary constituents. The bioavailability of heme and nonheme iron is influenced by dietary factors, including ascorbic acid, coffee, and whole grains (9). Body iron stores also are important determinants of intestinal absorption of heme and nonheme iron (10).The expanding literature suggests that iron influences glucose metabolism (3). Statistically significant positive associations of dietary iron intake, particularly heme iron, with incident type 2 diabetes has been reported (6–8). These epidemiological associations are supported by findings documenting increased risks of incident type 2 diabetes among individuals with elevated serum ferritin concentrations (6,11). The relationship between nonheme iron intake and type 2 diabetes, however, has been far less consistent. Some (7), but not all (8), investigators have reported inverse associations of incident type 2 diabetes and dietary nonheme iron intake.Although there have been several studies investigating the possible role of dietary iron and body iron stores on glucose metabolism, only a few have enrolled pregnant women, and the results have been inconsistent (12–14). The effect of iron supplement use on gestational diabetes mellitus (GDM) risk also is controversial (14,15). To the best of our knowledge, no previous study has examined the associations of dietary heme and nonheme iron with the risk of GDM. Given mounting available experimental and epidemiological evidence from studies of men and nonpregnant women supporting associations of heme iron and risk of type 2 diabetes, we hypothesized that higher preconceptional and early pregnancy dietary heme iron intake may be associated with increased GDM risk. We also hypothesized that diets high in nonheme iron may be associated with reduced GDM risk. We investigated these hypotheses among a well-characterized prospective cohort of pregnant women.     

Associations between media consumption habits, physical activity, socioeconomic status, and glycemic control in children, adolescents, and young adults with type 1 diabetes

OBJECTIVE

To evaluate the relationship between media consumption habits, physical activity, socioeconomic status, and glycemic control in youths with type 1 diabetes.

RESEARCH DESIGN AND METHODS

In the cross-sectional study, self-report questionnaires were used to assess media consumption habits, physical activity, and socioeconomic status in 296 children, adolescents, and young adults with type 1 diabetes. Clinical data and HbA_1c levels were collected. Risk factors were analyzed by multiple regression.

RESULTS

Youths with type 1 diabetes (aged 13.7 ± 4.1 years, HbA_1c 8.7 ± 1.6%, diabetes duration 6.1 ± 3.3 years) spent 2.9 ± 1.8 h per day watching television and using computers. Weekly physical activity was 5.1 ± 4.5 h. Multiple regression analysis identified diabetes duration, socioeconomic status, and daily media consumption time as significant risk factors for glycemic control.

CONCLUSIONS

Diabetes duration, socioeconomic status, and daily media consumption time, but not physical activity, were significant risk factors for glycemic control in youths with type 1 diabetes.The pivotal Diabetes Control and Complications Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC) study demonstrate that poor glycemic control is associated with an increased risk of developing complications in type 1 diabetes (1). Various factors contributing to glycemic control have been identified (2). Immutable parameters such as age, sex, diabetes duration, and socioeconomic status have a major effect on metabolic control (2–6). Lower socioeconomic status is an important determinant for poor glycemic control (4,5). Modifiable factors influencing metabolic control are diabetes-related knowledge, frequency of blood glucose monitoring, and daily insulin dose (3,4,6,7). Lastly, psychosocial parameters are important in achieving good glycemic control (3–5,8–10). The influence of physical activity on metabolic control is unclear (9,11,12).Recent research addresses the influence of modern life habits on general health. Youths spend more and more time watching television and using computers. Many studies suggest that sedentary behaviors such as watching television lead to obesity in children (13,14). In one study in youths with type 1 diabetes, Margeirsdottir et al. (15) showed that poor metabolic control was associated with extensive television watching. However, the authors did not examine other covariables, such as socioeconomic status, which is associated with both glycemic control and media consumption (4,5,16,17). Hence, the aim of this study was to examine the impact of media consumption habits, physical activity, and socioeconomic status on glycemic control in youths with type 1 diabetes.     

Physical Activity Before and During Pregnancy and Risk of Gestational Diabetes Mellitus: A meta-analysis

OBJECTIVE

Gestational diabetes mellitus (GDM) is one of the most common complications of pregnancy and is associated with a substantially elevated risk of adverse health outcomes for both mothers and offspring. Physical activity may contribute to the prevention of GDM and thus is crucial for dissecting the vicious circle involving GDM, childhood obesity, and adulthood obesity, and diabetes. Therefore, we aimed to systematically review and synthesize the current evidence on the relation between physical activity and the development of GDM.

RESEARCH DESIGN AND METHODS

Medline, EMBASE, and Cochrane Reviews were searched from inception to 31 March 2010. Studies assessing the relationship between physical activity and subsequent development of GDM were included. Characteristics including study design, country, GDM diagnostic criteria, ascertainment of physical activity, timing of exposure (prepregnancy or early pregnancy), adjusted relative risks, CIs, and statistical methods were extracted independently by two reviewers.

RESULTS

Our search identified seven prepregnancy and five early pregnancy studies, including five prospective cohorts, two retrospective case-control studies, and two cross-sectional study designs. Prepregnancy physical activity was assessed in 34,929 total participants, which included 2,813 cases of GDM, giving a pooled odds ratio (OR) of 0.45 (95% CI 0.28–0.75) when the highest versus lowest categories were compared. Exercise in early pregnancy was assessed in 4,401 total participants, which included 361 cases of GDM, and was also significantly protective (0.76 [95% CI 0.70–0.83]).

CONCLUSIONS

Higher levels of physical activity before pregnancy or in early pregnancy are associated with a significantly lower risk of developing GDM.Gestational diabetes mellitus (GDM) is one of the most common complications of pregnancy, affecting ∼7% of all pregnancies in the U.S. (i.e., >200,000 cases annually) (1), and this number is increasing as the prevalence of obesity among women at reproductive age escalates (2–4). GDM is associated with a significantly elevated risk for short-term and long-term complications for both mothers and offspring. Women with GDM have an increased risk for perinatal morbidity and impaired glucose tolerance and type 2 diabetes in the years after pregnancy (5,6). Children of women with GDM are more likely to be obese and have impaired glucose tolerance and diabetes in childhood and early adulthood (1). In a recent meta-analysis of randomized trials on the effect of treatment for GDM, various interventions for blood glucose control, including diet, glucose monitoring, insulin use, and pharmaceutical interventions, did not significantly reduce the risk for adverse perinatal and neonatal end points, including cesarean section and perinatal or neonatal death (7). Collectively, these data indicate that prevention of GDM altogether could be crucial for avoiding its associated adverse health outcomes.Physical activity has long been known for its role in improving glucose homeostasis through its direct or indirect impact on insulin sensitivity via several mechanisms. For instance, physical activity has independent effects on glucose disposal by increasing both insulin-mediated and non–insulin-mediated glucose disposal (8,9). Physical activity can also exert long-term effects on improvement in insulin sensitivity through increased fat-free mass (10). Furthermore, the benefits of preventing or delaying the onset of type 2 diabetes among nonpregnant individuals have been reported repeatedly (11,12). Therefore, physical activity may have the potential for preventing GDM and related adverse health outcomes. However, evidence for its impact on GDM has not been systematically synthesized. The aim of this systematic review and meta-analysis was to assemble the current evidence for the relationship between physical activity and the development of GDM.     

Gestational Diabetes Mellitus: Simplifying the International Association of Diabetes and Pregnancy diagnostic algorithm using fasting plasma glucose

OBJECTIVE

To determine the impact of the International Association of Diabetes and Pregnancy Study Group (IADPSG) criteria on 1) gestational diabetes mellitus (GDM) diagnosis compared with the American Diabetes Association (ADA) criteria and 2) the fasting plasma glucose (FPG) to predict GDM.

RESEARCH DESIGN AND METHODS

In 10,283 pregnant women undergoing a 75-g oral glucose tolerance test (OGTT) for universal screening of GDM, two FPG thresholds (of the OGTT) were used to rule in and to rule out GDM.

RESULTS

The IADPSG and ADA criteria identified GDM in 3,875 (37.7%) women and 1,328 (12.9%) women, respectively (P < 0.0005). FPG thresholds of ≥5.1 mmol/l ruled in GDM in 2,975 (28.9%) women with 100% specificity, while <4.4 mmol/l ruled out GDM in 2,228 (21.7%) women with 95.4% sensitivity. FPG independently could have avoided the OGTT in 5,203 (50.6%) women.

CONCLUSIONS

The IADPSG criteria increased GDM prevalence nearly threefold. By circumventing a significant number of OGTTs, an initial FPG can greatly simplify the IADPSG diagnostic algorithm.The scourge of gestational diabetes mellitus (GDM) is the lack of an international agreement on the screening and diagnosis among the pre-eminent diabetes, obstetric, and health care organizations (1). Therefore, without a globally accepted guideline, the diagnosis of GDM causes a great deal of clinical confusion (2). In March 2010, the International Association of Diabetes and Pregnancy Study Group (IADPSG) issued consensus guidelines to potentially attain a single approach for GDM diagnosis worldwide (3).The inconsistency in GDM diagnosis is evident in the United Arab Emirates (UAE), which has the second highest prevalence of type 2 diabetes (18.7%) in the world (4). GDM in the UAE varies from 7.9 to 24.9%, depending on which of the six well-accepted criteria are used for diagnosis (2). The popular American Diabetes Association (ADA) criteria (5) demonstrates a prevalence of 10.6–14.7% (2,6–8). In this population, multiple studies have confirmed that the initial fasting plasma glucose (FPG) result of the oral glucose tolerance test (OGTT) is excellent in determining the need to continue with the OGTT (6,9–10); however, its efficiency depends on the criteria used for GDM diagnosis (6). The aim of this study was to determine, in this high-risk population, the impact of the new IADPSG criteria on 1) the diagnosis of GDM compared with the ADA criteria and 2) the FPG to predict GDM in order to decide whether to proceed with the OGTT.     

Body Composition Is Normal in Term Infants Born to Mothers With Well-Controlled Gestational Diabetes Mellitus

OBJECTIVE

This study aims to describe body composition in term infants of mothers with gestational diabetes mellitus (GDM) compared with infants of mothers with normal glucose tolerance (NGT).

RESEARCH DESIGN AND METHODS

This cross-sectional study included 599 term babies born at Royal Prince Alfred Hospital, Sydney, Australia. Neonatal body fat percentage (BF%) was measured within 48 h of birth using air-displacement plethysmography. Glycemic control data were based on third-trimester HbA_1c levels and self-monitoring blood glucose levels. Associations between GDM status and BF% were investigated using linear regression adjusted for relevant maternal and neonatal variables.

RESULTS

Of 599 babies, 67 (11%) were born to mothers with GDM. Mean ± SD neonatal BF% was 7.9 ± 4.5% in infants with GDM and 9.3 ± 4.3% in infants with NGT, and this difference was not statistically significant after adjustment. Good glycemic control was achieved in 90% of mothers with GDM.

CONCLUSIONS

In this study, neonatal BF% did not differ by maternal GDM status, and this may be attributed to good maternal glycemic control.Fetal growth and development is affected through the altered intrauterine environment of gestational diabetes mellitus (GDM) (1,2). An accurate method to characterize overgrowth is by estimation of body composition, which includes fat mass (FM) and fat-free mass (FFM) (3,4). Previous studies have shown that increases in FM are present in infants of GDM pregnancies, regardless of their weight for gestational age (1,5). The gold-standard method of measuring body composition changes is air-displacement plethysmography (ADP) (4,6,7). The aim of this study was to describe body composition and anthropometric measurements at birth in term infants of women with GDM compared with infants of mothers with normal glucose tolerance (NGT) levels.     

How Many Sonograms Are Needed to Reliably Predict the Absence of Fetal Overgrowth in Gestational Diabetes Mellitus Pregnancies?

OBJECTIVE

Serial measurements of the fetal abdominal circumference have been used to guide metabolic management of pregnancies complicated by gestational diabetes mellitus (GDM). A reduction in the number of repeat ultrasound examinations would save resources. Our purpose was to determine the number of serial abdominal circumference measurements per patient necessary to reliably predict the absence of fetal overgrowth.

RESEARCH DESIGN AND METHODS

Women who had GDM were asked to return for repeat ultrasound at 3- to 4-week intervals starting at initiation of care (mean 26.9 ± 5.7 weeks). Maternal risk factors associated with fetal overgrowth were determined.

RESULTS

A total of 4,478 ultrasound examinations were performed on 1,914 subjects (2.3 ± 1.2 per pregnancy). Of the 518 women with fetal abdominal circumference >90th percentile, it was diagnosed in 73.9% with the first ultrasound examination at entry and in 13.1% with the second ultrasound examination. Of the fetuses, 85.9 and 86.9% of the fetuses were born non-large for gestational age (LGA) when abdominal circumference was <90th percentile at 24–27 weeks and 28–32 weeks, respectively, and 88.0% were born non-LGA when both scans showed normal growth. For those women who had no risk factors for fetal overgrowth (risk factors: BMI >30 kg/m², history of macrosomia, and fasting glucose > 100 mg/dl), the accuracy of prediction of a non-LGA neonate was 90.0, 89.5, and 95.2%. The predictive ability did not increase with more than two normal scans.

CONCLUSIONS

The yield of sonographic diagnosis of a large fetus drops markedly after the finding of a fetal abdominal circumference <90th percentile on two sonograms, which excludes with high reliability the risk of a LGA newborn. The ability was enhanced in women who had no risk factors for neonatal macrosomia.The recommendations for diagnosis and treatment of gestational diabetes mellitus (GDM) of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus (1) suggest consideration of fetal growth patterns to guide metabolic management of pregnant women with GDM. Estimation of fetal weight, particularly at term and in fetuses with high neonatal weight, is not as precise as is desirable (2). However, enlarged size (3–6) and accelerated growth velocity of the fetal abdominal circumference in the third trimester is known to predict large-for-gestational-age (LGA) birth weight (7). Previous randomized studies have demonstrated that measurement of the fetal abdominal circumference throughout pregnancy in women who have GDM is useful to identify pregnancies at high risk for fetal overgrowth and therefore in need of intensified intervention (8–11). On the other side, relaxed glycemic goals had been allowed in women with sonographic evidence of normal fetal growth. Besides saving insulin therapy, this approach reduced the rate of fetal growth restriction in the fetuses of those women. Published protocols for fetal growth–based management require sonographic determination of fetal abdominal circumference at the time of diagnosis of GDM (8–11) followed by repeat examinations at 2 (11)- to 4-week intervals (9,10). Serial sonographic examinations are costly and require the time and expertise of experienced ultrasonographers and/or physicians.The purpose of our study was to determine the number of sequential ultrasound examinations necessary not to miss development of an enlarged abdominal circumference during pregnancy and to assure a low risk for a LGA neonate with a great degree of certainty when the scans suggest normal fetal growth. In addition, we wished to evaluate whether the absence of maternal risk factors for neonatal macrosomia would enhance the accuracy of the ultrasound examination predicting a non-LGA neonate.     

Racial/ethnic disparities in the prevalence of gestational diabetes mellitus by BMI

OBJECTIVE

To examine whether the association between gestational diabetes mellitus (GDM) and BMI category varies by racial/ethnic group.

RESEARCH DESIGN AND METHODS

In a cohort of 123,040 women without recognized pregravid diabetes who delivered babies between 1995 and 2006 at Kaiser Permanente of Northern California, we examined racial/ethnic disparities in the prevalence of GDM by BMI category and the population-attributable risk (PAR) associated with overweight/obesity.

RESULTS

Among all racial/ethnic groups, the age-adjusted prevalence of GDM increased with increasing BMI (kg/m²) category. However, Asian and Filipina women had a prevalence of GDM of 9.9 and 8.5%, respectively, at a BMI of 22.0–24.9 kg/m², whereas in Hispanic, non-Hispanic white, and African American women, the prevalence of GDM was >8.0% at a higher BMI, such as 28–30, 34–36, and ≥37 kg/m², respectively. The estimated PARs suggest that the percentage of GDM that could be prevented if all pregnant women were of normal weight (BMI <25.0 kg/m²) ranging from 65% for African American women to only 23% among Asian women.

CONCLUSIONS

Clinicians should be aware that the BMI thresholds for increased risk of GDM varies by racial/ethnic group and that the risk is high even at relatively low BMI cutoffs in Asian and Filipina women. Asian women may benefit from different prevention strategies in addition to weight management.Gestational diabetes mellitus (GDM) is carbohydrate intolerance with onset of or first recognition during pregnancy and is one of the most common pregnancy complications in the U.S. GDM is associated with increased risk for perinatal morbidity (1,2), and, in the long-term, women with GDM have an almost sevenfold increased risk of developing type 2 diabetes after pregnancy (3). The prevalence of GDM has increased in all racial/ethnic groups, and this has been observed in several populations in recent decades (4,5). Recent data suggest that the association between glucose and risk of adverse outcomes is continuous; gestational impaired glucose tolerance (IGT) is also associated with both pregnancy complications (6) and subsequent diabetes and cardiometabolic risk (7).Race/ethnicity and obesity are the two strongest independent risk factors for GDM (8–11). However, the demographic distribution of obesity (highest among African Americans and lowest among Asians) does not mirror the demographic distribution of GDM (lowest among African Americans and highest among Asians) (12). Yet there is ongoing debate surrounding the definition of overweight and obesity in Asian populations: the World Health Organization proposed a BMI cutoff of 23.0 kg/m² for overweight among Asians in 2000 (13), compared with a cutoff of 25.0 kg/m² for non-Asian populations. More recently, the World Health Organization stated that the definition of overweight in Asians likely varies depending on the outcome of interest (14). Currently, little is known about racial disparities in the risk of GDM by BMI categories.In a cohort of 123,040 women without recognized pregravid diabetes who delivered babies between 1995 and 2006 at Kaiser Permanente of Northern California (KPNC), we examined racial/ethnic disparities in the prevalence of GDM and IGT in pregnancy by BMI category and the estimated proportion of cases that could be prevented if overweight/obesity in pregnant women were eliminated (the population-attributable risk [PAR]).     

Disproportionate Body Composition and Neonatal Outcome in Offspring of Mothers With and Without Gestational Diabetes Mellitus

OBJECTIVE

High birth weight is a risk factor for neonatal complications. It is not known if the risk differs with body proportionality. The primary aim of this study was to determine the risk of adverse pregnancy outcome in relation to body proportionality in large-for-gestational-age (LGA) infants stratified by maternal gestational diabetes mellitus (GDM).

RESEARCH DESIGN AND METHODS

Population-based study of all LGA (birth weight [BW] >90th percentile) infants born to women with GDM (n = 1,547) in 1998–2007. The reference group comprised LGA infants (n = 83,493) born to mothers without diabetes. Data were obtained from the Swedish Birth Registry. Infants were categorized as proportionate (P-LGA) if ponderal index (PI) (BW in grams/length in cm³) was ≤90th percentile and as disproportionate (D-LGA) if PI >90th percentile. The primary outcome was a composite morbidity: Apgar score 0–3 at 5 min, birth trauma, respiratory disorders, hypoglycemia, or hyperbilirubinemia. Logistic regression analysis was used to obtain odds ratios (ORs) for adverse outcomes.

RESULTS

The risk of composite neonatal morbidity was increased in GDM pregnancies versus control subjects but comparable between P- and D-LGA in both groups. D-LGA infants born to mothers without diabetes had significantly increased risk of birth trauma (OR 1.19 [95% CI 1.09–1.30]) and hypoglycemia (1.23 [1.11–1.37]). D-LGA infants in both groups had significantly increased odds of Cesarean section.

CONCLUSIONS

The risk of composite neonatal morbidity is significantly increased in GDM offspring. In pregnancies both with and without GDM, the risk of composite neonatal morbidity is comparable between P- and D-LGA.High birth weight (BW), in both diabetic and nondiabetic pregnancies, is associated with increased risk of maternal and perinatal complications as well as long-term adverse health consequences for the offspring (1–10). Gestational diabetes and maternal obesity are well-established risk factors for high BW (11–14). In pregnancies with gestational diabetes mellitus (GDM), reported rates of high-BW infants range between 15 and 62.5% (15–18), corresponding to a several-fold increased risk compared with the general obstetric population (19). Complications associated with high BW include excessive maternal bleeding, prolonged labor, instrumental delivery, Cesarean section, perineal tears, stillbirth, neonatal birth trauma, low Apgar scores, acute respiratory disorders, hypoglycemia, and neonatal death (1–7). Irrespective of BW, GDM offspring face an excess risk of future morbidities (20–23). However, the risk may be even further increased in infants born with fetal macrosomia (24,25).The definition for high BW is not consistent. Current definitions are based on either absolute BW (>4,000 or 4,500 g) and referred to as fetal macrosomia or BW in relation to gestational age and sex (large for gestational age [LGA], BW >90th or 97.5th percentile). It is unclear which of these definitions best predicts the risk of adverse outcome. None of the current definitions take into account body proportionality, i.e., the relation between the infant''s BW and birth length (BL). The ponderal index (PI; i.e., BW in grams/BL in cm³) is a marker for body proportionality, and at a population level, the PI is a useful estimate of body proportionality when BW and BL are routinely collected. Fetal macrosomia or LGA in infants born to mothers with GDM and/or obesity is characterized by a disproportionate body composition with high BW in relation to BL (26) and increased fat mass (27–29).The primary aim of this study was to determine the risk of adverse pregnancy outcome in relation to body proportionality in LGA infants (BW >90th percentile) stratified by maternal GDM status. We hypothesized that infants with a disproportionate body composition, most likely as a consequence of fetal hyperinsulinemia, would have an increased risk of perinatal complications compared with those with a proportionate body composition.     

Low Prepregnancy Adiponectin Concentrations Are Associated With a Marked Increase in Risk for Development of Gestational Diabetes Mellitus

OBJECTIVE

To examine whether circulating total and high–molecular weight (HMW) adiponectin concentrations, measured before pregnancy, are associated with subsequent risk of gestational diabetes mellitus (GDM).

RESEARCH DESIGN AND METHODS

This was a nested case-control study among women who participated in the Kaiser Permanente Northern California Multiphasic Health Check-up exam (1984–1996) with a serum sample obtained and who had a subsequent pregnancy (1984–2009). Eligible women were free of recognized diabetes. Case subjects were the 256 women who developed GDM. Two control subjects were selected for each case and matched for year of blood draw, age at exam, age at pregnancy, and number of intervening pregnancies.

RESULTS

Compared with the highest quartile of adiponectin, the risk of GDM increased with decreasing quartile (odds ratio [OR] 1.5 [95% CI 0.7–2.9], 3.7 [1.9–7.2], and 5.2 [2.6–10.1]; P_trend <0.001) after adjustment for family history of diabetes, BMI, parity, race/ethnicity, cigarette smoking, and glucose and insulin concentrations. Similar estimates were observed for HMW (P_trend <0.001). The combined effects of having total adiponectin levels below the median (<10.29 mg/mL) and being overweight or obese (BMI ≥25.0 kg/m²) were associated with a sevenfold increased risk of GDM compared with normal-weight women with adiponectin levels above the median (OR 6.7 [95% CI 3.6–12.5]).

CONCLUSIONS

Prepregnancy low adiponectin concentrations, a marker of decreased insulin sensitivity and altered adipocyte endocrine function, is associated with reduced glucose tolerance during pregnancy and may identify women at high risk for GDM to target for early intervention.Gestational diabetes mellitus (GDM), defined as glucose intolerance with onset or first diagnosis during pregnancy, is a common complication of pregnancy. Women with a history of GDM have a sevenfold increased risk of developing type 2 diabetes after delivery (1), and the children of women with GDM are more likely to be obese and develop diabetes (2,3). The underlying etiology of GDM appears to be similar to the physiological abnormalities that characterize diabetes outside of pregnancy and is thought to be due to an inability of the pancreatic β-cells to compensate for the increased insulin resistance induced by pregnancy (4,5). The extent to which insulin resistance or reduced insulin sensitivity leading to GDM occurs even years before pregnancy has not been determined in population-based studies. There is increasing interest in identifying prepregnancy risk factors and biomarkers for GDM to inform future preconception prevention strategies, given the proven success of specific prevention strategies for type 2 diabetes in high-risk populations (6).Adiponectin is an abundant adipocyte-derived hormone demonstrated to have actions consistent with protection against insulin resistance, inflammation, and atherosclerosis (7). Total adiponectin circulates in the bloodstream as three discrete complexes: a lower–molecular weight trimer, a mid–molecular weight hexamer, and a high–molecular weight (HMW) complex (8). Some evidence suggests that HMW adiponectin is the isoform that mediates the insulin-sensitizing and antiatherogenic effects (9,10). Prospective studies examining adiponectin and incident type 2 diabetes reported that lower circulating total adiponectin concentrations were associated with a higher risk of type 2 diabetes in a dose-response relationship (11). Both total adiponectin (12) and HMW adiponectin (13) are known to decrease significantly in normal pregnancies in response to decreased insulin sensitivity; therefore, it is important to determine whether prepregnancy levels of adiponectin are related to subsequent risk of GDM in order to clarify the temporal sequence of the association. The aim of this study is to examine the association between prepregnancy total and HMW adiponectin concentrations and the risk of developing GDM and to determine whether these associations are independent of known metabolic risk factors for GDM.     

TRAF-interacting Protein (TRIP): A Novel Component of the Tumor Necrosis Factor Receptor (TNFR)- and CD30-TRAF Signaling Complexes That Inhibits TRAF2-mediated NF-κB Activation

Through their interaction with the TNF receptor–associated factor (TRAF) family, members of the tumor necrosis factor receptor (TNFR) superfamily elicit a wide range of biological effects including differentiation, proliferation, activation, or cell death. We have identified and characterized a novel component of the receptor–TRAF signaling complex, designated TRIP (TRAF-interacting protein), which contains a RING finger motif and an extended coiled-coil domain. TRIP associates with the TNFR2 or CD30 signaling complex through its interaction with TRAF proteins. When associated, TRIP inhibits the TRAF2-mediated NF-κB activation that is required for cell activation and also for protection against apoptosis. Thus, TRIP acts as a receptor–proximal regulator that may influence signals responsible for cell activation/proliferation and cell death induced by members of the TNFR superfamily.Members of the TNF receptor (TNFR)¹ superfamily play important roles in the induction of diverse signals leading to cell growth, activation, and apoptosis (1). Whether the signals induced by a given receptor leads to cell activation or death is, however, highly cell-type specific and tightly regulated during differentiation of cells. For example, the TNFRs can exert costimulatory signals for proliferation of naive lymphocytes but also induce death signals required for deletion of activated T lymphocytes (1). The cytoplasmic domains of these receptors lack intrinsic catalytic activity and also exhibit no significant homology to each other or to other known proteins. Exceptions to this include Fas(CD95) and TNFR1 that share a significant homology within an 80–amino acid region of their cytoplasmic tails (called the “death domain”; 2, 3). Therefore, it is suggested that the TNFR family members can initiate different signal transduction pathways by recruiting different types of intracellular signal transducers to the receptor complex (1).Indeed, several types of intracellular signal transducers have been identified that initiate distinct signal transduction pathways when recruited to the members of TNFR superfamily (4–19). Recent biochemical and molecular studies showed that a class of signal-transducing molecules are recruited to Fas(CD95) or TNFR1 via interaction of the death domains (2, 3, 6, 12, 17, 20). For example, Fas(CD95) and TNFR1 recruit FADD(MORT1)/RIP or TRADD/FADD (MORT1)/RIP through the interactions of their respective death domains (2, 3, 6, 12, 17, 20, 21). Clustering of these signal transducers leads to the recruitment of FLICE/ MACH, and subsequently, to cell death (13, 14).The TNFR family members can also recruit a second class of signal transducers called TRAFs (TNFR-associated factor), some of which are responsible for the activation of NF-κB or JNK (9, 20, 22). TRAF proteins were identified by their biochemical ability to interact with TNFR2, CD40, CD30, or LT-βR (4, 5, 10, 11, 15, 23–27). These receptors interact directly with TRAFs via a short stretch of amino acids within their cytoplasmic tails, but do not interact with the death domain containing proteins (4, 5, 15, 24–27). To date, five members of the TRAF family have been identified as signaling components of the TNFR family members. All TRAF members contain a conserved TRAF domain, ∼230 amino acids in length, that is used for either homo- or heterooligomerization among the TRAF family, for interactions with the cytoplasmic regions of the TNFR superfamily, or for interactions with downstream signal transducers (4, 5, 8, 10, 11, 19, 23–25, 28). In addition to the TRAF domain, most of the TRAF family members contain an NH₂-terminal RING finger and several zinc finger structures, which appear to be important for their effector functions (4, 5, 10, 11, 23–25).Several effector functions of TRAFs were revealed by recent experiments based on a transfection system. TRAF2, first identified by its interaction with TNFR2 (4), was subsequently shown to mediate NF-κB activation induced by two TNF receptors, CD40 and CD30 (9, 28–30). TRAF5 was also implicated in NF-κB activation mediated by LTβR (10), whereas TRAF3 (also known as CRAF1, CD40bp, or LAP1; references 5, 11, 24, and 25) was shown to be involved in the regulation of CD40-mediated CD23 upregulation in B cells (5). The role of other TRAF members in the TNFR family–mediated signal transduction is not clear. They may possess some effector functions as yet to be revealed, or work as adapter proteins to recruit different downstream signal transducers to the receptor complex. For example, TRAF1 is required for the recruitment of members of the cellular inhibitor of apoptosis protein (c-IAP) family to the TNFR2-signaling complex (7). In addition to the signal transduction by the TNFR family members, TRAFs may regulate other receptor-mediated signaling pathways. For example, TRAF6 is a component of IL-1 receptor (IL1R)–signaling complex, in which it mediates the activation of NF-κB by IL-1R (31). Since TRAFs form homo- or heterooligomers, it is suggested that the repertoire of TRAF members in a given cell type may differentially affect the intracellular signals triggered by these receptors. This may be accomplished by the selective interaction of TRAFs with a specific set of downstream signal transducers. Although many aspects of TRAF-mediated effector functions leading to cellular activation have been defined, it needs to be determined whether TRAF proteins will also mediate the apoptotic signals induced by the “death-domain-less” members of the TNFR superfamily (1, 27, 32–36).Here we report the isolation and characterization of a novel component of the TNFR superfamily/TRAFs signaling complex, named TRIP (TRAF-interacting protein). TRIP associates with the receptor/TRAF signaling complex, and inhibits the TRAF2-mediated NF-κB activation. Biochemical studies indicate that TRIP associates with the TNFR2 or CD30 receptor complex via its interaction with TRAF proteins, suggesting a model which can explain why the ligation of these receptors can promote different cell fates: proliferation or death.