Screening for biomarkers predictive of gestational diabetes mellitus Increased Maternal Plasma Leptin in Early Pregnancy and Risk of Gestational Diabetes Mellitus Prediction of gestational diabetes in obese pregnant women from the UK Pregnancies Better Eating and Activity (UPBEAT) pilot trial. Mendelian Randomisation and Causal Inference in Observational Epidemiology Prediction of gestational diabetes mellitus by maternal factors and biomarkers at 11 to 13 weeks. Leptin and Soluble Leptin Receptor Levels in Plasma and Risk of Type 2 Diabetes in U.S. Women Lower Adiponectin Levels at First Trimester of Pregnancy Are Associated With Increased Insulin Resistance and Higher Risk of Developing Gestational Diabetes Mellitus Circulating adiponectin levels and risk of type 2 diabetes in the Japanese Longitudinal Analysis of Maternal Serum Leptin Levels during Pregnancy, at Birth and Up To Six Weeks after Birth: Relation to Body Mass Index, Skinfolds, Sex Steroids and Umbilical Cord Blood Leptin Levels Variations of tumor necrosis factor-alpha, leptin and adiponectin in mid-trimester of gestational diabetes mellitus. TNFα dynamics during the oral glucose tolerance test vary according to the level of insulin resistance in pregnant women.
Screening for glucose intolerance during pregnancy provides an opportunity to offer management to those women diagnosed with gestational diabetes mellitus . However , there is a need to diagnose gestational diabetes early to minimize exposure of the developing fetus to suboptimal conditions and prevent perinatal complications and their sequelae . The purpose of this study was to identify potential biomarkers for impending gestational diabetes that appear in the plasma before impaired glucose tolerance . Pregnant women were prospect ively recruited to the study and blood was collected at the first antenatal visit and at the time of routine oral glucose tolerance test . Women diagnosed with gestational diabetes were matched with an equal number of normal pregnant ( control ) women . Biomarkers under investigation included endocrine and metabolic hormones , cytokines and chemokines , and surrogate markers of oxidative stress . Compared to controls , women with gestational diabetes exhibited elevated plasma insulin and reduced plasma adiponectin concentrations at 28 weeks gestation . Significant differences in insulin and adiponectin concentrations were also observed in plasma at 11 weeks gestation . Bivariate logistic regression analysis showed that both insulin and adiponectin are associated with subsequent development of gestational diabetes . Plasma insulin and adiponectin concentrations , when measured at 11 weeks , may be predictive of impending gestational diabetes . Further studies are warranted to determine the reliability of these biomarkers OBJECTIVE : Emerging evidence suggests that leptin , an adipocyte-derived hormone , may have independent direct effects on both insulin secretion and action , in addition to its well documented effects on appetite and energy expenditure . Some , but not all , previously published studies suggest that maternal leptin concentrations may be increased in pregnancies complicated by gestational diabetes mellitus ( GDM ) . We examined the association between plasma leptin concentration and GDM risk . METHODS : Women were recruited before 16 weeks of gestation and were followed up until delivery .  Maternal plasma leptin concentrations  ( collected at 13 weeks of gestation ) were measured by using immunoassay . We used generalized linear models to estimate relative risks and 95 % confidence intervals . RESULTS : GDM developed in 5.7 % of the cohort ( 47 of 823 ) . Elevated leptin concentrations were positively associated with GDM risk ( P for trend < .001 ) . After adjusting for maternal prepregnancy adiposity and other confounders , women with leptin concentrations of 31.0 ng/mL or higher experienced a 4.7-fold increased risk of GDM ( 95 % confidence interval 1.2 , 18.0 ) as compared with women who had concentrations of 14.3 ng/mL or lower . We noted a strong linear component of trend in risk of GDM with increasing maternal plasma leptin concentration . Each 10-ng/mL increase in the leptin concentration was associated with a 20 % increase in GDM risk ( relative risk 1.2 ; 95 % confidence interval 1.0 , 1.3 ) . CONCLUSIONS : Hyperleptinemia , independent of maternal adiposity , in early pregnancy appears to be predictive of an increased risk of GDM later in pregnancy . Additional larger prospect i ve cohort studies are needed to confirm and more precisely assess the etiologic importance of hyperleptinemia in pregnancy . LEVEL OF EVIDENCE : AIM To examine the prediction of gestational diabetes in obese women using routine clinical measures and measurement of biomarkers related to insulin resistance in the early second trimester . METHODS A total of 117 obese pregnant women participating in a pilot trial of a complex intervention of dietary advice and physical activity  were studied . Blood sample s were obtained at recruitment ( 15⁺⁰-17⁺⁶ weeks ' gestation ) and demographic , clinical history and anthropometric measures recorded . The biomarkers analysed were plasma lipids ( HDL cholesterol , LDL cholesterol , triglycerides ) , high-sensitivity C-reactive protein , alanine transaminase , aspartate transaminase , ferritin , fructosamine , insulin , adiponectin , tissue plasminogen activator , interleukin-6 , visfatin and leptin . Univariate and logistic regression analyses were performed to determine independent predictors and area under the receiver-operating curve was calculated for the model . RESULTS Of the 106 participants included in the analysis , 29 ( 27.4 % ) developed gestational diabetes . Participants with gestational diabetes were older ( P = 0.002 ) , more often of parity ≥ 2 , had higher systolic ( P = 0.02 ) and diastolic blood pressure ( P = 0.02 ) and were more likely to be black ( P = 0.009 ) . Amongst the blood biomarkers measured , plasma adiponectin alone remained independently associated with gestational diabetes in adjusted models ( P = 0.002 ) . The area under the receiver-operating curve for clinical factors alone ( 0.760 ) increased significantly ( area under the curve 0.834 , chi-square statistic ( 1 ) = 4.00 , P = 0.046 ) with the addition of adiponectin . CONCLUSIONS A combination of routinely measured clinical factors and adiponectin measured in the early second trimester in obese women may provide a useful approach to the prediction of gestational diabetes . Validation in a large prospect i ve study is required to determine the usefulness of this algorithm in clinical practice Nuala Sheehan and colleagues describe how Mendelian r and omization provides an alternative way of dealing with the problems of observational studies , especially confounding OBJECTIVE To develop a model for the prediction of gestational diabetes mellitus ( GDM ) from maternal characteristics and biochemical markers at 11 to 13 weeks ' gestation . METHODS A prospect i ve screening study on early prediction of pregnancy complications ( n = 11 , 464 ) , including 297 ( 2.6 % ) cases of GDM was used to create the predictive model of GDM based on maternal characteristics .  Maternal serum concentrations of adiponectin , follistatin-like-3 ( FSTL3 ) and sex hormone-binding globulin ( SHBG ) were measured in a case-control study of 80 women who developed GDM and 300 controls . RESULTS In the screening study , maternal age , body mass index , racial origin , previous history of GDM and macrosomic neonate were significant independent predictors of future GDM . In the GDM group , compared to controls , the median multiple of the normal median adiponectin ( 0.66 ; IQR : 0.5 - 0.9 vs 1.02 ; IQR : 0.7 - 1.29 ) and SHBG ( 0.81 ; IQR : 0.6 - 1.04 vs 1.02 ; IQR : 0.8 - 1.2 ) was lower ( p < 0.05 ) , but FSTL3 was not significantly different . In screening for GDM by maternal characteristics , the detection rate was 61.6 % at a false-positive rate of 20 % and the detection increased to 74.1 % by the addition of adiponectin and SHBG . CONCLUSION First-trimester screening for GDM can be provided by a combination of maternal characteristics and biomarkers OBJECTIVE We prospect ively examined plasma levels of leptin and soluble leptin receptor ( sOB-R ) , as well as their interactions with other diabetes risk factors , in relation to type 2 diabetes to eluci date the complex relation between these two biomarkers and diabetes risk . RESEARCH DESIGN AND METHODS Of 32,826 Nurses ' Health Study participants who provided blood sample s during 1989–1990 , 1,054 incident case subjects of type 2 diabetes were identified and confirmed during 1990–2004 and 1,254 matched control subjects were selected .  Plasma leptin and sOB-R levels were measured among these participants . RESULTS After multivariate adjustment for BMI , lifestyle practice s , and dietary factors , sOB-R levels were significantly associated with a lower risk of type 2 diabetes . In comparison with women in the lowest quintile , the ORs ( 95 % CI ) of developing type 2 diabetes were 0.73 ( 0.55–0.96 ) , 0.51 ( 0.38–0.68 ) , 0.42 ( 0.31–0.57 ) , and 0.39 ( 0.28–0.54 ; P for trend < 0.0001 ) for women in the second to fifth quintiles of sOB-R levels , respectively . In contrast , plasma leptin levels were not significantly associated with the risk of type 2 diabetes : The OR ( 95 % CI ) was 0.82 ( 0.62–1.10 ; P for trend = 0.46 ) comparing the highest with the lowest quintile of leptin levels . sOB-R levels were consistently associated with a decreased risk of type 2 diabetes at various levels of leptin or high-molecular-weight adiponectin . CONCLUSIONS These data suggest a strong inverse association between plasma sOB-R levels and risk of type 2 diabetes , independent of BMI , leptin , and adiponectin levels OBJECTIVE To evaluate the associations between  adiponectin levels and 1 ) the risk of developing gestational diabetes mellitus ( GDM ) , and 2 ) insulin resistance/sensitivity , β-cell function , and compensation indices in a prospect i ve cohort representative of the general population of pregnant women . RESEARCH DESIGN AND METHODS We performed anthropometric measurements and collected blood sample s at 1st ( 6–13 weeks ) and 2nd ( 24–28 weeks ) trimesters . Diagnosis of GDM was made at 2nd trimester based on a 75-g oral glucose tolerance test ( International Association of the Diabetes and Pregnancy Study Groups criteria ) .  Insulin was measured ( ELISA ; Luminex ) to estimate homeostasis model assessment of insulin resistance ( HOMA-IR ) , β-cell function ( HOMA-B ) , insulin sensitivity ( Matsuda index ) , insulin secretion ( AUCinsulin/glucose ) , and β-cell compensation ( insulin secretion sensitivity index-2 ) . Adiponectin  was measured by radioimmunoassay . RESULTS Among the 445 participants included in this study , 38 women developed GDM . Women who developed GDM had lower 1st-trimester adiponectin levels ( 9.67 ± 3.84 vs. 11.92 ± 4.59 µg/mL in women with normal glucose tolerance ) . Lower adiponectin levels were associated with higher risk of developing GDM ( OR , 1.12 per 1 µg/mL decrease of adiponectin levels ; P = 0.02 , adjusted for BMI and HbA1c at 1st trimester ) . Adiponectin levels at 1st and 2nd trimesters were associated with HOMA-IR ( both : r = −0.22 , P < 0.0001 ) and Matsuda index ( r = 0.28 , P < 0.0001 , and r = 0.29 , P < 0.0001 ) . After adjustment for confounding factors , we found no significant association with HOMA-B and AUCinsulin/glucose . CONCLUSIONS Pregnant women with lower adiponectin levels at 1st trimester have higher levels of insulin resistance and are more likely to develop GDM independently of adiposity or glycemic measurements Background : Adiponectin has anti-inflammatory and insulin-sensitizing properties . Prospect i ve studies have consistently shown a lower risk of type 2 diabetes among those with higher circulating adiponectin levels . Objective : We examined prospect ively the association between serum adiponectin levels and type 2 diabetes risk among Japanese workers , taking visceral fat mass into account . Subjects and methods : Subjects were 4591 Japanese employees who attended a comprehensive health screening in 2008 ; had biochemical data including serum adiponectin ; were free of diabetes at baseline ; and received health screening in 2011 .  Multiple logistic regression analysis was used to examine the association between adiponectin and incidence of diabetes among overall subjects , as well as subgroups . Stratified analyses were carried out according to variables including visceral fat area ( VFA ) . Results : During 3 years of follow-up , 217 diabetic cases were newly identified . Of these , 87 % had a prediabetes at baseline . Serum adiponectin level was significantly , inversely associated with incidence of diabetes , with odds ratios ( 95 % confidence interval ) adjusted for age , sex , family history , smoking , alcohol drinking , physical activity and body mass index ( BMI ) for the lowest through highest quartile of adiponectin of 1 ( reference ) , 0.79 ( 0.55–1.12 ) , 0.60 ( 0.41–0.88 ) and 0.40 ( 0.25–0.64 ) , respectively ( P-value for trend < 0.01 ) . This association was material ly unchanged with adjustment for VFA instead of BMI . After further adjustment for both homeostasis model assessment of insulin resistance and hemoglobin A1c , however , the association became statistically nonsignificant ( P-value for trend=0.18 ) . Risk reduction associated with higher adiponectin levels was observed in both participants with and without obesity or insulin resistance at baseline . Conclusions : Results suggest that higher levels of circulating adiponectin are associated with a lower risk of type 2 diabetes , independently of overall and intra-abdominal fat deposition , and that adiponectin may confer a benefit in both persons with and without insulin resistance Leptin is an important regulator of body fat mass and energy expenditure during adult life . The mechanisms by which maternal and fetal weight are regulated during pregnancy are poorly understood . In order to gain more insight into a potential role of leptin during gestation , a prospect i ve , longitudinal study was carried out to measure leptin concentrations in maternal serum of 29 healthy women during pregnancy up to 6 weeks after birth and also in umbilical cord blood of their newborns .  Leptin concentrations were measured using a specific RIA . In addition , estradiol , testosterone , and sex hormone binding globulin were determined using commercially available RIAs . The mothers ’ skinfolds were determined at four sites using a Holtain caliper . Leptin levels increased continuously during pregnancy and reached 25.8 ± 14.7 ng/ml at 38–40 weeks . At birth , leptin concentrations were 23.5 ± 15.4 ng/ml . Three days after delivery a significant decrease of leptin levels to 10.6 ± 6.0 ng/ml was observed . Six weeks after birth the leptin concentration in maternal serum was 13.8 ± 8.6 ng/ml . At birth , maternal serum levels were significantly higher than levels in cord blood and did not correlate with leptin levels in cord blood or neonatal weight . Furthermore , leptin levels did not correlate with maternal sex steroids and sex hormone binding globulin levels . At 6–8 weeks of pregnancy , maternal leptin serum levels correlated significantly with BMI ( r = 0.81 ) . The correlation coefficients ( leptin vs. BMI ) dropped with increasing gestational age and at birth only a poor correlation persisted ( r = 0.50 ) . Six weeks after birth there was again a high correlation between leptin levels in maternal serum and BMI ( r = 0.76 ) . Subscapular skinfold thickness was correlated to leptin concentrations in maternal serum during the whole period of the investigation . In conclusion , maternal leptin levels continuously increased from 6–8 weeks up to 38–40 weeks of pregnancy . Maternal leptin levels decreased dramatically after birth . Six weeks after delivery , leptin levels were comparable to the values measured at the beginning of pregnancy . We hypothesize that leptin might play an important role during pregnancy and fetal development BACKGROUND Many cytokines have been found to increase the insulin resistance during pregnancy complicated by glucose metabolism disorder . This study aim ed to investigate which comes first , the changes of some cytokines or the abnormal glucose metabolism . METHODS This nested case-control study was undertaken from January 2004 to March 2005 . Twenty-two women with gestational diabetes mellitus ( GDM ) , 10 with gestational impaired glucose tolerance ( GIGT ) , and 20 healthy pregnant women were chosen from the women who had visited the antenatal clinics and had blood sample s prospect ively taken and kept during their visit . The levels of tumor necrosis factor-alpha ( TNF-alpha ) , leptin and adiponectin were determined . One-way ANOVA analysis and bivariate correlation analysis were used to assess the laboratory results and their relationship with body mass index ( BMI ) . RESULTS Women with GDM have the highest values of TNF-alpha and leptin and the lowest value of adiponectin compared with those with GIGT and the healthy controls ( P < 0.01 ) at 14 - 20 weeks of gestation . This was also found when these women progressed to 24 - 32 weeks . The significantly increased levels of TNF-alpha and leptin and the decreased level of adiponectin were found at the different periods of gestation within the same group . Positive correlation was shown between the levels of TNF-alpha and leptin at the two periods of gestation with the BMI at 14 - 20 weeks , while adiponectin was negatively correlated ( P < 0.05 ) . CONCLUSIONS The concentrations of TNF-alpha , leptin and adiponectin may change before the appearance of the abnormal glucose level during pregnancy . Further studies are required to verify the mechanism of this alteration and whether the three cytokines can be predictors for GDM at an early stage of pregnancy INTRODUCTION TNFα is suspected to play a role in inflammation and insulin resistance leading to higher risk of metabolic impairment . Controversies exist concerning the role of TNFα in gestational insulin resistance . We investigated the interrelations between TNFα and insulin resistance in a large population -based cohort of pregnant women . METHODS Women ( n = 756 ) were followed prospect ively at 5 - 16 weeks and 24 - 28 weeks of pregnancy .  Anthropometric measures and blood sample s were collected at both visits . A 75-g oral glucose tolerance test ( OGTT ) was conducted at the second trimester to assess insulin sensitivity status ( homeostasis model of assessment of insulin resistance and Matsuda index ) . TNFα was measured at the first trimester ( nonfasting ) and at each time point of the OGTT . RESULTS Participants were 28.4 ± 4.4 years old and had a mean body mass index of 25.5 ± 5.5 kg/m(2 ) at first trimester . Median TNFα levels were 1.56 ( interquartile range , 1.18 - 2.06 ) pg/mL at first trimester and 1.61 ( interquartile range , 1.12 - 2.13 ) pg/mL at second trimester ( 1 h after glucose load ) . At second trimester , higher TNFα levels were associated with higher insulin resistance index levels ( r = 0.37 and -0.30 for homeostasis model of assessment of insulin resistance and Matsuda index , respectively ; P < .0001 ) , even after adjustment for age , body mass index , triglycerides , and adiponectin . Women with higher insulin resistance showed a continuing decrease in TNFα levels during the OGTT , whereas women who were more insulin sensitive showed an increase in TNFα at hour 1 and a decrease at hour 2 of the test . CONCLUSION Higher insulin resistance is associated with higher levels of circulating TNFα at first and second trimesters of pregnancy . TNFα level dynamics during an OGTT at second trimester vary according to insulin-resistance state
OBJECTIVE We aim ed to systematic ally review available literature linking adipokines to gestational diabetes mellitus ( GDM ) for a comprehensive underst and ing of the roles of adipokines in the development of GDM .