Original Research
First-Trimester Serum Fatty Acid-Binding Protein 4 and Subsequent Gestational Diabetes Mellitus Wen-Jun Tu, MD, PhD, Min Guo, and Chen-Wei Fu, MD, PhD
MD,
Xiao-Dong Shi,
OBJECTIVE: To examine whether plasma fatty acidbinding protein 4 concentrations, measured in the first trimester, are associated with gestational diabetes mellitus (GDM). METHODS: This prospective, multicenter cohort study was conducted at three maternity centers in two cities (Harbin and Beijing) in China from July 2015 to June 2016. Data for fasting plasma glucose and fatty acid-binding protein 4 concentrations in the first trimester and onestep GDM screening with a 75-g oral glucose tolerance test performed between 24 and 28 weeks of gestation were collected and analyzed. RESULTS: Plasma from women in the first trimester was available for 1,150 women, of whom 135 (11.7%) developed GDM. The GDM distribution across the fatty acid-binding protein 4 quartiles ranged from 3.8% (first quartile) to 21.6% (fourth quartile). In multivariate models comparing the second (quartile 2), third, and fourth quartiles against the first quartile of fatty acid-binding protein 4, concentrations of fatty acid-binding protein 4 in quartile 2, quartile
From the Institute of Radiation Medicine, China Academy of Medical Science & Peking Union Medical College, Tianjin, the Department of Laboratory, China Rehabilitation Research Center, Beijing, the Departments of Endocrinology and Gynaecology and Obstetrics, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, and the Department of Gynaecology and Obstetrics, Peking Union Medical College Hospital, Beijing, China. Supported by the CAMS Innovation Fund for Medical Science (No. 2017-I2M1–021) and National Natural Science Foundation of Heilongjiang. The authors thank the nurses, physicians, and patients who participated in our study and the staff of the central laboratories of the hospitals. Each author has indicated that he or she has met the journal’s requirements for authorship. Corresponding author: Qiang Liu, PhD, No. 238, Baiti Road, Tianjin 300192, PR China; email: [email protected]. Financial Disclosure The authors did not report any potential conflicts of interest. © 2017 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0029-7844/17
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MD,
Yan Cai,
MD,
Qiang Liu,
PhD,
3, and quartile 4 were associated with the development of GDM with respective associated adjusted odds ratios (95% CIs) of 1.76 (1.21–2.58), 2.36 (1.55–4.29), and 3.57 (1.99– 6.11). A significant difference in the area under receiver operating characteristic curve between established risk factors alone and the addition of fatty acid-binding protein 4 concentrations was observed (difference 0.042 [95% CI 0.028–0.055]; P5.03). CONCLUSIONS: Higher fatty acid-binding protein 4 concentrations in the first trimester visit were associated with increased risk of GDM and might be useful in identifying women at risk for GDM for early prevention strategies. (Obstet Gynecol 2017;0:1–6) DOI: 10.1097/AOG.0000000000002310
G
estational diabetes mellitus (GDM) is a common pregnancy-related health condition that may result in negative outcomes for mothers and their offspring, both short and long term.1 Fatty acid-binding protein 4, an intracellular lipid chaperone that is highly expressed in adipocytes and macrophages, may play an important role in lipid transport and the progression of atherosclerosis.2 Abnormalities in the level of fatty acid-binding protein 4 have been correlated with the development of adiposity,3 metabolic syndrome,4 atherosclerosis,5 and preeclampsia.6 Studies in animal models suggested that fatty acidbinding protein 4 may be important in glucose homeostasis. Deletion of the AFABP gene protected mice from insulin resistance and hyperinsulinemia associated with both diet-induced obesity7 and genetic obesity.8 In humans, serum fatty acid-binding protein 4 concentrations have been shown to be associated with poor glucose control in type 2 diabetes.9 Furthermore, Zhang et al8 found higher fatty acid-binding protein 4 concentrations in women with GDM during mid- to late gestation. In this prospective cohort study, we assessed the association
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1
of first-trimester fatty acid-binding protein 4 concentrations and the subsequent development of GDM.
MATERIALS AND METHODS This prospective, multicenter cohort study was conducted at three maternity centers in two cities (Harbin and Beijing) in China from July 2015 to June 2016. We recruited nulliparous women at least 18 years old with singleton gestations in the first trimester. We excluded women with pregestational diabetes, alcohol abuse, renal failure, chronic disease (such as heart disease, cancer, hepatitis, and arthritis), consumption of drugs that interact with glucose or lipid metabolism, those with lost blood samples, and those who terminated their pregnancies. Before the initiation of the study, it was approved by the ethics committee of the Harbin Medical University. All participants were informed of the study protocol, and written informed consent was obtained before inclusion. Maternal–pregnancy characteristics were collected and recorded at the first prenatal visit. Gestational age was established by ultrasonography. Specific details about physical activity were assessed by a validated questionnaire adapted from the Canadian Community Health Survey.10 At the first prenatal visit, participants underwent venous fasting plasma glucose and fatty acid-binding protein 4 testing after at least 8 hours of fasting. Plasma fatty acid-binding protein 4 concentrations were analyzed using a commercially available enzyme-linked immunosorbent assay by personnel blinded to GDM status. The lower detection limit for fatty acid-binding protein 4 was presented as 5 ng/mL, and the detection range was 5–100 ng/mL. Interassay and intraassay coefficients of variation were 3.3–7.5% and 2.4–4.5%, respectively. Triglyceride, cholesterol, high-density lipoprotein, low-density lipoprotein, insulin, C-reactive protein (CRP), and insulin were tested using standard detection methods. Between 24 and 28 weeks of gestation, study participants underwent a 75-g oral glucose tolerance test. The diagnosis of GDM was made when any one of the following values was met or exceeded: fasting 91.8 mg/dL or greater, 1 hour 180.0 mg/dL or greater, and 2 hours 153.0 mg/dL or greater.11 Results were expressed as percentages for categorical variables and as medians (interquartile ranges) for the continuous variables. Univariate data on demographic and clinical features were compared by MannWhitney U test or x2 test as appropriate. In addition, 95% CIs for incidence of GDM were calculated. Univariate and multivariate regression analyses were performed to investigate the relationship between
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concentrations of fatty acid-binding protein 4 and GDM. Crude models and multivariate models were developed for the adjustment of all associated factors and reported as odds ratios (ORs). For multivariate analysis, variables included the factors significant in univariate regression analysis (maternal age, body mass index [BMI, calculated as weight (kg)/[height (m)]2], pre-existing cardiovascular disease, family history of diabetes, and blood levels of cholesterol, high-density lipoprotein, insulin, fasting plasma glucose, and CRP). For a more detailed exploration of fatty acid-binding protein 4 and GDM, a multivariate analysis model was created to estimate adjusted ORs and 95% CIs of GDM for fatty acidbinding protein 4 quartiles (with the first quartile as the referent). Receiver operating characteristic curves were developed to assess area under the curve (AUC). Integrated discrimination improvement and net reclassification improvement indices were calculated to investigate the utility of adding fatty acid-binding protein 4 to recognized risk factors for GDM.12 All statistical analysis was performed with SPSS for Windows 21.0 and the ROCR package 1.0–2. Statistical significance was defined as P,.05.
RESULTS A total of 1,150 women were included in the study (Fig. 1; Table 1), of whom 135 developed GDM (11.7%; 95% CI 9.9–13.6%). Median concentration
Fig. 1. Study flow diagram. GDM, gestational diabetes mellitus. Tu. Fatty Acid-Binding Protein 4 Levels and Risk of GDM. Obstet Gynecol 2017.
Fatty Acid-Binding Protein 4 Levels and Risk of GDM
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of fatty acid-binding protein 4 was higher in women who developed GDM than those who did not (23.9 [interquartile range 17.6–32.2] ng/mL compared with 16.8 [12.3–23.0] ng/mL; Z58.532, P,.001; Fig. 2). Plasma fatty acid-binding protein 4 was positively associated with BMI (r53.01; P,.001), CRP (r50.268; P,.001), fasting plasma glucose (r50.249, P,.001), and insulin (r50.188, P5.002) and negatively correlated with high-density lipoprotein (r520.196; P5.001). Furthermore, fatty acid-binding protein 4 concentration did not vary significantly by age, risk factors, ethnicity, smoking, physical activity, triglyceride, cholesterol, or low-density lipoprotein (P..05 for all). The distribution of GDM across fatty acidbinding protein 4 quartiles ranged from 3.8% (first quartile) to 21.6% (fourth quartile; Table 2). For each one-unit increase of plasma concentration of fatty acid-binding protein 4, the unadjusted and adjusted risk of GDM increased by 11% (OR 1.11 [95% CI 1.08–1.03]) and 6% (1.06 [1.02–1.111]), respectively. In multivariate models comparing the second (quartile 2), third (quartile 3), and fourth quartiles (quartile 4) against the first quartile (quartile 1) of fatty acidbinding protein 4, concentrations of fatty acid-binding
protein 4 in quartile 2, quartile 3, and quartile 4 were associated with the development of GDM with associated increased risks of 76%, 176%, and 257%, respectively, by quartile (Table 2). The independent association of fatty acid-binding protein 4 with the development of GDM was confirmed using the likelihood ratio test (P,.001). In a multivariate model using the fourth quartile of fatty acid-binding protein 4 compared with quartile 1 through quartile 3 together with the clinical variables, the marker displayed prognostic information (GDM: OR for quartile 4 2.15 [95% CI 1.52–3.01; P5.009]). Based on the results of receiver operating characteristic curve, the optimal cutoff value of plasma fatty acid-binding protein 4 concentration for the subsequent development of GDM was estimated at 18.5 ng/mL, which yielded a sensitivity of 81.8% and a specificity of 71.2% with the AUC at 0.733 (95% CI 0.698–0.786). Furthermore, an increased risk of GDM was associated with fatty acid-binding protein 4 concentration 18.6 ng/mL or greater (adjusted OR 2.88, 95% CI 1.93–4.22) in multivariable models. The AUC for fatty acid-binding protein 4 alone to predict GDM was 0.733. By contrast, the AUC
Table 1. Maternal and Clinical Characteristics of the Included Women at the Time of Fatty Acid-Binding Protein 4 Assessment Characteristic n Maternal age (y) BMI (kg/m2) Obesity Ethnicity—Han Chinese Pre-existing hypertension Pre-existing CVD Family history of diabetes—yes History of spontaneous abortion Smoker—yes Gestational age (wk; range) Physical activity (kcal/kg d) Plasma samples Insulin (milli-international units/L) Total cholesterol (mmol/L) HDL cholesterol (mmol/L) Triglyceride (mmol/L) FPG (mg/dL) CRP (mg/L) FA-BP4 (ng/mL)
Women With GDM
Women Without GDM
P*
Padjusted†
135 29 (25–34) 28.1 (26.5–29.7) 31 (23.0) 119 (88.1) 14 (10.4) 13 (9.6) 46 (34.1) 12 (8.9) 18 (13.3) 6 (3–10) 1.4 (0.8–2.0)
1,015 25 (22–27) 24.5 (23.4–27.8) 121 (11.9) 905 (89.2) 68 (6.7) 45 (4.4) 145 (14.3) 83 (8.2) 121 (11.9) 6 (3–10) 1.3 (0.7–1.9)
.031 ,.001 .001 .704 .119 .010 ,.001 .778 .636 .365 .406
.106 .001 .005 .825 .335 .106 .008 .866 .778 .569 .615
16.2 (13.8–19.7) 4.98 (4.33–5.19) 1.50 (1.31–1.90) 1.32 (1.13–1.60) 96.3 (90.4–105.8) 4.8 (3.6–7.0) 23.9 (17.6–32.2)
12.5 (9.2–15.6) 4.70 (4.05–4.873) 1.89 (1.52–2.18) 1.23 (1.06–1.49) 83.3 (77.6–91.6) 4.1 (3.0–5.9) 16.8 (12.3–23.1)
,.001 .033 .010 .086 ,.001 .001 ,.001
.003 .194 .022 .332 .003 .022 ,.001
GDM, gestational diabetes mellitus; BMI, body mass index; CVD, cardiovascular disease; HDL, high-density lipoprotein; FPG, fasting plasma glucose; CRP, C-reactive protein; FA-BP4, fatty acid-binding proteins. Data are median (interquartile range) or n (%) unless otherwise specified. * P value tested by x2 or Mann–Whitney test. † Logistic regression adjusted for maternal age, BMI, pre-existing CVD, family history of diabetes, and blood levels of cholesterol, HDL, insulin, FPG, and CRP.
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Fatty Acid-Binding Protein 4 Levels and Risk of GDM 3
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GDM (integrated P5.01).
discrimination
improvement
DISCUSSION
Fig. 2. Plasma concentration of fatty acid-binding protein 4 (FA-BP4) in different groups, Mann–Whitney U test. All data are medians and interquartile ranges (IQRs). The median plasma concentration of FA-BP4 was significantly higher in women in whom gestational diabetes mellitus (GDM) later developed compared with those in whom it did not (23.9 [IQR 17.6–32.2] ng/mL compared with 16.8 [IQR 12.3–23.0] ng/mL; Z58.532, P,.001). Tu. Fatty Acid-Binding Protein 4 Levels and Risk of GDM. Obstet Gynecol 2017.
was 0.818 with the addition of fatty acid-binding protein 4 to the established model containing known risk factors for GDM (Table 3). The addition of fatty acid-binding protein 4 increased the correct classification of GDM development (net reclassification improvement statistic P,.001) and fatty acidbinding protein 4 concentration provided increased discrimination between women with and without Table 2. Odds Ratios for Gestational Diabetes Mellitus According to Fatty Acid-Binding Protein 4 Quartile at the First Visit FA-BP4 Quartile* 1 2 3 4
GDM
(n5287) (n5288) (n5288) (n5287)
11 24 38 62
(3.8) (8.3) (13.2) (21.6)
Unadjusted OR (95% CI)†
Adjusted OR (95% CI)†‡
Ref. 2.28 (1.10–4.75) 3.81 (1.91–7.62) 6.91 (3.56–13.44)
Ref. 1.76 (1.21–2.58) 2.36 (1.55–4.29) 3.57 (1.99–6.11)
FA-BP4, fatty acid-binding proteins; GDM, gestational diabetes mellitus; OR, odds ratio. Data are n (%) unless otherwise specified. * Plasma levels of FA-BP4 in quartile 1 (less than 12.8 ng/mL), quartile 2 (12.8–17.6 ng/mL), quartile 3 (17.7–24.4 ng/mL), and quartile 4 (greater than 24.4 ng/mL). † P value for the trend ,.001. ‡ Adjusted for maternal age, body mass index, pre-existing cardiovascular disease, family history of diabetes, and blood levels of cholesterol, high-density lipoprotein, insulin, fasting plasma glucose, and C-reactive protein.
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We have shown that higher circulating plasma fatty acid-binding protein 4 concentrations in the first trimester are associated with an increased risk for the development of GDM. On the basis of the present investigation, further research should be carried out to establish whether there is a causal relationship between fatty acid-binding protein 4 and GDM not only identifying fatty acid-binding protein 4 as an independent risk factor for GDM, but even potentially verifying that the removal or minimization of exposure to fatty acid-binding protein 4 would reduce the risk of GDM. There are only a few studies published to date that explored fatty acid-binding protein 4 concentrations in relationship to GDM. A cross-sectional study13 showed that fatty acid-binding protein 4 concentrations in the GDM group were significantly higher than those of controls and that fatty acid-binding protein 4 was an independent risk factor for increased insulin resistance. However, in another cross-sectional study, no apparent difference was observed regarding the concentration of fatty acid-binding protein 4 in women with GDM and those with normal glucose tolerance.14 In this study, maternal fatty acid-binding protein 4 concentrations were obviously upregulated in the first trimester in women who later developed GDM. Similarly, another study15 supports our finding that maternal fatty acid-binding protein 4 concentrations are significantly higher in women with GDM than those without. Numerous factors are suggested to be involved in the pathogenesis and potentially responsible for explaining mechanisms of GDM, including increased maternal weight,16 CRP17 as well as a progressive increase in glucose and insulin resistance.18 For example, the risk of GDM is suggested to be increased 1.3– 3.8 times in obese women compared with women with normal BMIs.19 In this study, obesity and higher concentrations of CRP, glucose, and insulin were also associated with an increased risk of developing GDM. Fatty acid-binding protein 4 is expressed in the cytoplasm of mature adipocytes and is a serum biomarker associated with obesity and insulin resistance, which is critical for the regulation of the transport and accumulation of fatty acids and triglyceride-rich lipoproteins during placental development.20,21 In fatty acid-binding protein 4 gene knockout mice with obesity caused by a high-fat diet, there was no occurrence of insulin resistance or diabetes, suggesting that fatty
Fatty Acid-Binding Protein 4 Levels and Risk of GDM
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Table 3. Plasma Fatty Acid-Binding Protein 4 Concentrations at Admission Prediction of Gestational Diabetes Mellitus AUROC GDM At admission
FA-BP4
Risk Factors*
Risk Factors With FA-BP4
Incremental Area (P)†
NRI (P)
IDI (P)
0.733
0.776
0.818
0.042 (.03)
0.106 (,.001)
0.044 (.01)
GDM, gestational diabetes mellitus; AUROC, area under the receiver operating characteristic curve; FA-BP4, fatty acid-binding proteins; NRI, net reclassification improvement; IDI, integrated discrimination improvement. * Established risk factors including: maternal age, body mass index, gestational age at sampling, smoking, ethnicity, pre-existing hypertension and cerebrovascular disease, history of spontaneous abortion, gestational weeks at admission, family history of diabetes, physical activity, and blood levels of cholesterol, high-density lipoprotein, triglyceride, insulin, fasting plasma glucose, and C-reactive protein. † Comparison of AUROCs: established risk factors without FA-BP4 levels compared with established risk factors with FA-BP4 levels.
acid-binding protein 4 might have a regulatory role in insulin sensitivity. There is also evidence that an elevation in fatty acid-binding protein 4 could contribute to the accumulation of short-chain free fatty acids and suppress the activity of relevant proteins in the phosphatidylinositol 39-kinase(PI3K)-AKT signal pathway, thereby inhibiting the presence of glucose oxidation and glycolysis and decreasing the uptake and utilization of glucose in human organs such as in muscle and the liver.22 The mechanism linking fatty acid-binding protein 4 with glucose homeostasis is not yet fully understood. In general, fatty acid-binding protein 4 may play an important role in lipid metabolism and insulin sensitivity. It is known that fatty acid-binding protein 4 can bind various intracellular fatty acids and probably mediates intracellular lipid trafficking between cellular compartments.23 It might also modulate the availability and composition of fatty acids in muscles and adipose tissues.24 As proved in a mice model, abnormal concentrations of fatty acid-binding protein 4 caused insulin resistance in male mice.7 In the myocytes and adipose tissues of mice, improved glucose homeostasis after the ablation of fatty acid-binding protein 4 was documented to result in the preferential accumulation of shorter chain fatty acids.7 The following limitations of our study must be taken into account. First, we acknowledge that the inclusion of Han Chinese women entirely may be a strength from the standpoint of data homogeneity but at the same time a limitation to generalizability. Second, functional promoter polymorphisms of fatty acid-binding protein 4 were not considered in this study and may be relevant to the association of fatty acid-binding protein 4 and the development of GDM.25 Lastly, our data, because of their observational nature, cannot speak to causality. Circulating plasma fatty acid-binding protein 4 concentrations in the first trimester are associated with an increased risk of the development of GDM in
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Chinese women and offer the potential to target women for interventions designed to lower their risk of developing GDM. REFERENCES 1. HAPO Study Cooperative Research Group, Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, et al. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 2008;358: 1991–2002. 2. Tu WJ, Zeng XW, Deng A, Zhao SJ, Luo DZ, Ma GZ, et al. Circulating FABP4 (fatty acid-binding protein 4) is a novel prognostic biomarker in patients with acute ischemic stroke. Stroke 2017;48:1531–8. 3. Xu A, Wang Y, Xu JY, Stejskal D, Tam S, Zhang J, et al. Adipocyte fatty acid–binding protein is a plasma biomarker closely associated with obesity and metabolic syndrome. Clin Chem 2006;52:405–13. 4. Terra X, Quintero Y, Auguet T, Porras JA, Hernández M, Sabench F, et al. FABP 4 is associated with inflammatory markers and metabolic syndrome in morbidly obese women. Eur J Endocrinol 2011;164:539–47. 5. Yeung DC, Xu A, Cheung CW, Wat NM, Yau MH, Fong CH, et al. Serum adipocyte fatty acid-binding protein levels were independently associated with carotid atherosclerosis. Arteriosclerosis Thromb Vasc Biol 2007;27:1796–802. 6. Scifres CM, Catov JM, Simhan H. Maternal serum fatty acid binding protein 4 (FABP4) and the development of preeclampsia. J Clin Endocrinol Metab 2012;97:E349–56. 7. Kralisch S, Klöting N, Ebert T, Kern M, Hoffmann A, Krause K, et al. Circulating adipocyte fatty acid-binding protein induces insulin resistance in mice in vivo. Obesity (Silver Spring) 2015;23:1007–13. 8. Zhang Y, Zhang H, Lu J, Zheng SY, Long T, Li YT, et al. Changes in serum adipocyte fatty acid-binding protein in women with gestational diabetes mellitus and normal pregnant women during mid- and late pregnancy. J Diabetes Investig 2016;7:797–804. 9. Tso AW, Xu A, Sham PC, Wat NM, Wang Y, Fong CH, et al. Serum adipocyte fatty acid-binding protein as a new biomarker predicting the development of type 2 diabetes: a 10-year prospective study in a Chinese cohort. Diabetes Care 2007;30:2667–72. 10. Qiu C, Sorensen TK, Luthy DA, Williams MA. A prospective study of maternal serum C-reactive protein (CRP) concentrations and risk of gestational diabetes mellitus. Paediatr Perinat Epidemiol 2004;18:377–84.
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11. Zhu W, Yang H, Wei Y, Yan J, Wang ZL, Li XL, et al. Evaluation of the value of fasting plasma glucose in the first prenatal visit to diagnose gestational diabetes mellitus in China. Diabetes Care 2013;36:586–90. 12. Pencina MJ, D’Agostino RB Sr, D’Agostino RB Jr, Vasan RS. Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med 2008;27:157–72. 13. Li YY, Xiao R, Li CP, Huangfu J, Mao JF. Increased plasma levels of FABP4 and PTEN is associated with more severe insulin resistance in women with gestational diabetes mellitus. Med Sci Monit 2015;21:426–31. 14. Ortega-Senovilla H, Schaefer-Graf U, Meitzner K, Abou-Dakn M, Graf K, Kintscher U, et al. Gestational diabetes mellitus causes changes in the concentrations of adipocyte fatty acidbinding protein and other adipocytokines in cord blood. Diabetes Care 2011;34:2061–6. 15. Ning H, Tao H, Weng Z, Zhao X. Plasma fatty acid-binding protein 4 (FABP4) as a novel biomarker to predict gestational diabetes mellitus. Acta Diabetol 2016;53:891–8. 16. Chu SY, Callaghan WM, Kim SY, Schmid CH, Lau J, England LJ, et al. Maternal obesity and risk of gestational diabetes mellitus. Diabetes Care 2007;30:2070–6. 17. Bossick AS, Peters RM, Burmeister C, Kakumanu N, Shill JE, Cassidy-Bushrow AE. Antenatal inflammation and gestational diabetes mellitus risk among pregnant African-American women. J Reprod Immunol 2016;115:1–5. 18. Ben-Haroush A, Yogev Y, Hod M. Epidemiology of gestational diabetes mellitus and its association with type 2 diabetes. Diabet Med 2004;21:103–13.
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19. Kim SY, Sappenfield W, Sharma AJ, Wilson HG, Bish CL, Salihu HM, et al. Racial/ethnic differences in the prevalence of gestational diabetes mellitus and maternal overweight and obesity, by nativity, Florida, 2004-2007. Obesity (Silver Spring) 2013;21:E33–40. 20. Biron-Shental T, Schaiff WT, Ratajczak CK, Bildirici I, Nelson DM, Sadovsky Y. Hypoxia regulates the expression of fatty acid-binding proteins in primary term human trophoblasts. Am J Obstet Gynecol 2007;197:516.e1–6. 21. Makkar A, Mishima T, Chang G, Scifres C, Sadovsky Y. Fatty acid binding protein-4 is expressed in the mouse placental labyrinth, yet is dispensable for placental triglyceride accumulation and fetal growth. Placenta 2014;35: 802–7. 22. Baar RA, Dinfelder CS, Smith LA, Bernlohr DA, Wu C, Lange AJ, et al. Investigation of in vivo fatty acid metabolism in AFABP/ap2(-/-) mice. Am J Physiol Endocrinol Metab 2005; 288:E187–93. 23. Coe NR, Bernlohr DA. Physiological properties and functions of intracellular fatty acid-binding proteins. Biochim Biophys Acta 1998;1391:287–306. 24. Maeda K, Cao H, Kono K, Gorgun CZ, Furuhashi M, Uysal KT, et al. Adipocyte/macrophage fatty acid binding proteins control integrated metabolic responses in obesity and diabetes. Cell Metab 2005;1:107–19. 25. Tuncman G, Erbay E, Hom X, De Vivo I, Campos H, Rimm EB, et al. Agenetic variant at the fatty acid-binding protein aP2 locus reduces the risk for hypertriglyceridemia, type 2 diabetes, and cardiovascular disease. Proc Natl Acad Sci U S A 2006;103: 6970–5.
Fatty Acid-Binding Protein 4 Levels and Risk of GDM
OBSTETRICS & GYNECOLOGY
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First-Trimester Serum Fatty Acid-Binding Protein 4 and Subsequent Gestational Diabetes Mellitus Wen-Jun Tu, MD, PhD, Min Guo, and Chen-Wei Fu, MD, PhD
MD,
Xiao-Dong Shi,
OBJECTIVE: To examine whether plasma fatty acidbinding protein 4 concentrations, measured in the first trimester, are associated with gestational diabetes mellitus (GDM). METHODS: This prospective, multicenter cohort study was conducted at three maternity centers in two cities (Harbin and Beijing) in China from July 2015 to June 2016. Data for fasting plasma glucose and fatty acid-binding protein 4 concentrations in the first trimester and onestep GDM screening with a 75-g oral glucose tolerance test performed between 24 and 28 weeks of gestation were collected and analyzed. RESULTS: Plasma from women in the first trimester was available for 1,150 women, of whom 135 (11.7%) developed GDM. The GDM distribution across the fatty acid-binding protein 4 quartiles ranged from 3.8% (first quartile) to 21.6% (fourth quartile). In multivariate models comparing the second (quartile 2), third, and fourth quartiles against the first quartile of fatty acid-binding protein 4, concentrations of fatty acid-binding protein 4 in quartile 2, quartile
From the Institute of Radiation Medicine, China Academy of Medical Science & Peking Union Medical College, Tianjin, the Department of Laboratory, China Rehabilitation Research Center, Beijing, the Departments of Endocrinology and Gynaecology and Obstetrics, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, and the Department of Gynaecology and Obstetrics, Peking Union Medical College Hospital, Beijing, China. Supported by the CAMS Innovation Fund for Medical Science (No. 2017-I2M1–021) and National Natural Science Foundation of Heilongjiang. The authors thank the nurses, physicians, and patients who participated in our study and the staff of the central laboratories of the hospitals. Each author has indicated that he or she has met the journal’s requirements for authorship. Corresponding author: Qiang Liu, PhD, No. 238, Baiti Road, Tianjin 300192, PR China; email: [email protected]. Financial Disclosure The authors did not report any potential conflicts of interest. © 2017 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0029-7844/17
VOL. 0, NO. 0, MONTH 2017
MD,
Yan Cai,
MD,
Qiang Liu,
PhD,
3, and quartile 4 were associated with the development of GDM with respective associated adjusted odds ratios (95% CIs) of 1.76 (1.21–2.58), 2.36 (1.55–4.29), and 3.57 (1.99– 6.11). A significant difference in the area under receiver operating characteristic curve between established risk factors alone and the addition of fatty acid-binding protein 4 concentrations was observed (difference 0.042 [95% CI 0.028–0.055]; P5.03). CONCLUSIONS: Higher fatty acid-binding protein 4 concentrations in the first trimester visit were associated with increased risk of GDM and might be useful in identifying women at risk for GDM for early prevention strategies. (Obstet Gynecol 2017;0:1–6) DOI: 10.1097/AOG.0000000000002310
G
estational diabetes mellitus (GDM) is a common pregnancy-related health condition that may result in negative outcomes for mothers and their offspring, both short and long term.1 Fatty acid-binding protein 4, an intracellular lipid chaperone that is highly expressed in adipocytes and macrophages, may play an important role in lipid transport and the progression of atherosclerosis.2 Abnormalities in the level of fatty acid-binding protein 4 have been correlated with the development of adiposity,3 metabolic syndrome,4 atherosclerosis,5 and preeclampsia.6 Studies in animal models suggested that fatty acidbinding protein 4 may be important in glucose homeostasis. Deletion of the AFABP gene protected mice from insulin resistance and hyperinsulinemia associated with both diet-induced obesity7 and genetic obesity.8 In humans, serum fatty acid-binding protein 4 concentrations have been shown to be associated with poor glucose control in type 2 diabetes.9 Furthermore, Zhang et al8 found higher fatty acid-binding protein 4 concentrations in women with GDM during mid- to late gestation. In this prospective cohort study, we assessed the association
OBSTETRICS & GYNECOLOGY
Copyright Ó by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
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of first-trimester fatty acid-binding protein 4 concentrations and the subsequent development of GDM.
MATERIALS AND METHODS This prospective, multicenter cohort study was conducted at three maternity centers in two cities (Harbin and Beijing) in China from July 2015 to June 2016. We recruited nulliparous women at least 18 years old with singleton gestations in the first trimester. We excluded women with pregestational diabetes, alcohol abuse, renal failure, chronic disease (such as heart disease, cancer, hepatitis, and arthritis), consumption of drugs that interact with glucose or lipid metabolism, those with lost blood samples, and those who terminated their pregnancies. Before the initiation of the study, it was approved by the ethics committee of the Harbin Medical University. All participants were informed of the study protocol, and written informed consent was obtained before inclusion. Maternal–pregnancy characteristics were collected and recorded at the first prenatal visit. Gestational age was established by ultrasonography. Specific details about physical activity were assessed by a validated questionnaire adapted from the Canadian Community Health Survey.10 At the first prenatal visit, participants underwent venous fasting plasma glucose and fatty acid-binding protein 4 testing after at least 8 hours of fasting. Plasma fatty acid-binding protein 4 concentrations were analyzed using a commercially available enzyme-linked immunosorbent assay by personnel blinded to GDM status. The lower detection limit for fatty acid-binding protein 4 was presented as 5 ng/mL, and the detection range was 5–100 ng/mL. Interassay and intraassay coefficients of variation were 3.3–7.5% and 2.4–4.5%, respectively. Triglyceride, cholesterol, high-density lipoprotein, low-density lipoprotein, insulin, C-reactive protein (CRP), and insulin were tested using standard detection methods. Between 24 and 28 weeks of gestation, study participants underwent a 75-g oral glucose tolerance test. The diagnosis of GDM was made when any one of the following values was met or exceeded: fasting 91.8 mg/dL or greater, 1 hour 180.0 mg/dL or greater, and 2 hours 153.0 mg/dL or greater.11 Results were expressed as percentages for categorical variables and as medians (interquartile ranges) for the continuous variables. Univariate data on demographic and clinical features were compared by MannWhitney U test or x2 test as appropriate. In addition, 95% CIs for incidence of GDM were calculated. Univariate and multivariate regression analyses were performed to investigate the relationship between
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concentrations of fatty acid-binding protein 4 and GDM. Crude models and multivariate models were developed for the adjustment of all associated factors and reported as odds ratios (ORs). For multivariate analysis, variables included the factors significant in univariate regression analysis (maternal age, body mass index [BMI, calculated as weight (kg)/[height (m)]2], pre-existing cardiovascular disease, family history of diabetes, and blood levels of cholesterol, high-density lipoprotein, insulin, fasting plasma glucose, and CRP). For a more detailed exploration of fatty acid-binding protein 4 and GDM, a multivariate analysis model was created to estimate adjusted ORs and 95% CIs of GDM for fatty acidbinding protein 4 quartiles (with the first quartile as the referent). Receiver operating characteristic curves were developed to assess area under the curve (AUC). Integrated discrimination improvement and net reclassification improvement indices were calculated to investigate the utility of adding fatty acid-binding protein 4 to recognized risk factors for GDM.12 All statistical analysis was performed with SPSS for Windows 21.0 and the ROCR package 1.0–2. Statistical significance was defined as P,.05.
RESULTS A total of 1,150 women were included in the study (Fig. 1; Table 1), of whom 135 developed GDM (11.7%; 95% CI 9.9–13.6%). Median concentration
Fig. 1. Study flow diagram. GDM, gestational diabetes mellitus. Tu. Fatty Acid-Binding Protein 4 Levels and Risk of GDM. Obstet Gynecol 2017.
Fatty Acid-Binding Protein 4 Levels and Risk of GDM
OBSTETRICS & GYNECOLOGY
Copyright Ó by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
of fatty acid-binding protein 4 was higher in women who developed GDM than those who did not (23.9 [interquartile range 17.6–32.2] ng/mL compared with 16.8 [12.3–23.0] ng/mL; Z58.532, P,.001; Fig. 2). Plasma fatty acid-binding protein 4 was positively associated with BMI (r53.01; P,.001), CRP (r50.268; P,.001), fasting plasma glucose (r50.249, P,.001), and insulin (r50.188, P5.002) and negatively correlated with high-density lipoprotein (r520.196; P5.001). Furthermore, fatty acid-binding protein 4 concentration did not vary significantly by age, risk factors, ethnicity, smoking, physical activity, triglyceride, cholesterol, or low-density lipoprotein (P..05 for all). The distribution of GDM across fatty acidbinding protein 4 quartiles ranged from 3.8% (first quartile) to 21.6% (fourth quartile; Table 2). For each one-unit increase of plasma concentration of fatty acid-binding protein 4, the unadjusted and adjusted risk of GDM increased by 11% (OR 1.11 [95% CI 1.08–1.03]) and 6% (1.06 [1.02–1.111]), respectively. In multivariate models comparing the second (quartile 2), third (quartile 3), and fourth quartiles (quartile 4) against the first quartile (quartile 1) of fatty acidbinding protein 4, concentrations of fatty acid-binding
protein 4 in quartile 2, quartile 3, and quartile 4 were associated with the development of GDM with associated increased risks of 76%, 176%, and 257%, respectively, by quartile (Table 2). The independent association of fatty acid-binding protein 4 with the development of GDM was confirmed using the likelihood ratio test (P,.001). In a multivariate model using the fourth quartile of fatty acid-binding protein 4 compared with quartile 1 through quartile 3 together with the clinical variables, the marker displayed prognostic information (GDM: OR for quartile 4 2.15 [95% CI 1.52–3.01; P5.009]). Based on the results of receiver operating characteristic curve, the optimal cutoff value of plasma fatty acid-binding protein 4 concentration for the subsequent development of GDM was estimated at 18.5 ng/mL, which yielded a sensitivity of 81.8% and a specificity of 71.2% with the AUC at 0.733 (95% CI 0.698–0.786). Furthermore, an increased risk of GDM was associated with fatty acid-binding protein 4 concentration 18.6 ng/mL or greater (adjusted OR 2.88, 95% CI 1.93–4.22) in multivariable models. The AUC for fatty acid-binding protein 4 alone to predict GDM was 0.733. By contrast, the AUC
Table 1. Maternal and Clinical Characteristics of the Included Women at the Time of Fatty Acid-Binding Protein 4 Assessment Characteristic n Maternal age (y) BMI (kg/m2) Obesity Ethnicity—Han Chinese Pre-existing hypertension Pre-existing CVD Family history of diabetes—yes History of spontaneous abortion Smoker—yes Gestational age (wk; range) Physical activity (kcal/kg d) Plasma samples Insulin (milli-international units/L) Total cholesterol (mmol/L) HDL cholesterol (mmol/L) Triglyceride (mmol/L) FPG (mg/dL) CRP (mg/L) FA-BP4 (ng/mL)
Women With GDM
Women Without GDM
P*
Padjusted†
135 29 (25–34) 28.1 (26.5–29.7) 31 (23.0) 119 (88.1) 14 (10.4) 13 (9.6) 46 (34.1) 12 (8.9) 18 (13.3) 6 (3–10) 1.4 (0.8–2.0)
1,015 25 (22–27) 24.5 (23.4–27.8) 121 (11.9) 905 (89.2) 68 (6.7) 45 (4.4) 145 (14.3) 83 (8.2) 121 (11.9) 6 (3–10) 1.3 (0.7–1.9)
.031 ,.001 .001 .704 .119 .010 ,.001 .778 .636 .365 .406
.106 .001 .005 .825 .335 .106 .008 .866 .778 .569 .615
16.2 (13.8–19.7) 4.98 (4.33–5.19) 1.50 (1.31–1.90) 1.32 (1.13–1.60) 96.3 (90.4–105.8) 4.8 (3.6–7.0) 23.9 (17.6–32.2)
12.5 (9.2–15.6) 4.70 (4.05–4.873) 1.89 (1.52–2.18) 1.23 (1.06–1.49) 83.3 (77.6–91.6) 4.1 (3.0–5.9) 16.8 (12.3–23.1)
,.001 .033 .010 .086 ,.001 .001 ,.001
.003 .194 .022 .332 .003 .022 ,.001
GDM, gestational diabetes mellitus; BMI, body mass index; CVD, cardiovascular disease; HDL, high-density lipoprotein; FPG, fasting plasma glucose; CRP, C-reactive protein; FA-BP4, fatty acid-binding proteins. Data are median (interquartile range) or n (%) unless otherwise specified. * P value tested by x2 or Mann–Whitney test. † Logistic regression adjusted for maternal age, BMI, pre-existing CVD, family history of diabetes, and blood levels of cholesterol, HDL, insulin, FPG, and CRP.
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GDM (integrated P5.01).
discrimination
improvement
DISCUSSION
Fig. 2. Plasma concentration of fatty acid-binding protein 4 (FA-BP4) in different groups, Mann–Whitney U test. All data are medians and interquartile ranges (IQRs). The median plasma concentration of FA-BP4 was significantly higher in women in whom gestational diabetes mellitus (GDM) later developed compared with those in whom it did not (23.9 [IQR 17.6–32.2] ng/mL compared with 16.8 [IQR 12.3–23.0] ng/mL; Z58.532, P,.001). Tu. Fatty Acid-Binding Protein 4 Levels and Risk of GDM. Obstet Gynecol 2017.
was 0.818 with the addition of fatty acid-binding protein 4 to the established model containing known risk factors for GDM (Table 3). The addition of fatty acid-binding protein 4 increased the correct classification of GDM development (net reclassification improvement statistic P,.001) and fatty acidbinding protein 4 concentration provided increased discrimination between women with and without Table 2. Odds Ratios for Gestational Diabetes Mellitus According to Fatty Acid-Binding Protein 4 Quartile at the First Visit FA-BP4 Quartile* 1 2 3 4
GDM
(n5287) (n5288) (n5288) (n5287)
11 24 38 62
(3.8) (8.3) (13.2) (21.6)
Unadjusted OR (95% CI)†
Adjusted OR (95% CI)†‡
Ref. 2.28 (1.10–4.75) 3.81 (1.91–7.62) 6.91 (3.56–13.44)
Ref. 1.76 (1.21–2.58) 2.36 (1.55–4.29) 3.57 (1.99–6.11)
FA-BP4, fatty acid-binding proteins; GDM, gestational diabetes mellitus; OR, odds ratio. Data are n (%) unless otherwise specified. * Plasma levels of FA-BP4 in quartile 1 (less than 12.8 ng/mL), quartile 2 (12.8–17.6 ng/mL), quartile 3 (17.7–24.4 ng/mL), and quartile 4 (greater than 24.4 ng/mL). † P value for the trend ,.001. ‡ Adjusted for maternal age, body mass index, pre-existing cardiovascular disease, family history of diabetes, and blood levels of cholesterol, high-density lipoprotein, insulin, fasting plasma glucose, and C-reactive protein.
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We have shown that higher circulating plasma fatty acid-binding protein 4 concentrations in the first trimester are associated with an increased risk for the development of GDM. On the basis of the present investigation, further research should be carried out to establish whether there is a causal relationship between fatty acid-binding protein 4 and GDM not only identifying fatty acid-binding protein 4 as an independent risk factor for GDM, but even potentially verifying that the removal or minimization of exposure to fatty acid-binding protein 4 would reduce the risk of GDM. There are only a few studies published to date that explored fatty acid-binding protein 4 concentrations in relationship to GDM. A cross-sectional study13 showed that fatty acid-binding protein 4 concentrations in the GDM group were significantly higher than those of controls and that fatty acid-binding protein 4 was an independent risk factor for increased insulin resistance. However, in another cross-sectional study, no apparent difference was observed regarding the concentration of fatty acid-binding protein 4 in women with GDM and those with normal glucose tolerance.14 In this study, maternal fatty acid-binding protein 4 concentrations were obviously upregulated in the first trimester in women who later developed GDM. Similarly, another study15 supports our finding that maternal fatty acid-binding protein 4 concentrations are significantly higher in women with GDM than those without. Numerous factors are suggested to be involved in the pathogenesis and potentially responsible for explaining mechanisms of GDM, including increased maternal weight,16 CRP17 as well as a progressive increase in glucose and insulin resistance.18 For example, the risk of GDM is suggested to be increased 1.3– 3.8 times in obese women compared with women with normal BMIs.19 In this study, obesity and higher concentrations of CRP, glucose, and insulin were also associated with an increased risk of developing GDM. Fatty acid-binding protein 4 is expressed in the cytoplasm of mature adipocytes and is a serum biomarker associated with obesity and insulin resistance, which is critical for the regulation of the transport and accumulation of fatty acids and triglyceride-rich lipoproteins during placental development.20,21 In fatty acid-binding protein 4 gene knockout mice with obesity caused by a high-fat diet, there was no occurrence of insulin resistance or diabetes, suggesting that fatty
Fatty Acid-Binding Protein 4 Levels and Risk of GDM
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Table 3. Plasma Fatty Acid-Binding Protein 4 Concentrations at Admission Prediction of Gestational Diabetes Mellitus AUROC GDM At admission
FA-BP4
Risk Factors*
Risk Factors With FA-BP4
Incremental Area (P)†
NRI (P)
IDI (P)
0.733
0.776
0.818
0.042 (.03)
0.106 (,.001)
0.044 (.01)
GDM, gestational diabetes mellitus; AUROC, area under the receiver operating characteristic curve; FA-BP4, fatty acid-binding proteins; NRI, net reclassification improvement; IDI, integrated discrimination improvement. * Established risk factors including: maternal age, body mass index, gestational age at sampling, smoking, ethnicity, pre-existing hypertension and cerebrovascular disease, history of spontaneous abortion, gestational weeks at admission, family history of diabetes, physical activity, and blood levels of cholesterol, high-density lipoprotein, triglyceride, insulin, fasting plasma glucose, and C-reactive protein. † Comparison of AUROCs: established risk factors without FA-BP4 levels compared with established risk factors with FA-BP4 levels.
acid-binding protein 4 might have a regulatory role in insulin sensitivity. There is also evidence that an elevation in fatty acid-binding protein 4 could contribute to the accumulation of short-chain free fatty acids and suppress the activity of relevant proteins in the phosphatidylinositol 39-kinase(PI3K)-AKT signal pathway, thereby inhibiting the presence of glucose oxidation and glycolysis and decreasing the uptake and utilization of glucose in human organs such as in muscle and the liver.22 The mechanism linking fatty acid-binding protein 4 with glucose homeostasis is not yet fully understood. In general, fatty acid-binding protein 4 may play an important role in lipid metabolism and insulin sensitivity. It is known that fatty acid-binding protein 4 can bind various intracellular fatty acids and probably mediates intracellular lipid trafficking between cellular compartments.23 It might also modulate the availability and composition of fatty acids in muscles and adipose tissues.24 As proved in a mice model, abnormal concentrations of fatty acid-binding protein 4 caused insulin resistance in male mice.7 In the myocytes and adipose tissues of mice, improved glucose homeostasis after the ablation of fatty acid-binding protein 4 was documented to result in the preferential accumulation of shorter chain fatty acids.7 The following limitations of our study must be taken into account. First, we acknowledge that the inclusion of Han Chinese women entirely may be a strength from the standpoint of data homogeneity but at the same time a limitation to generalizability. Second, functional promoter polymorphisms of fatty acid-binding protein 4 were not considered in this study and may be relevant to the association of fatty acid-binding protein 4 and the development of GDM.25 Lastly, our data, because of their observational nature, cannot speak to causality. Circulating plasma fatty acid-binding protein 4 concentrations in the first trimester are associated with an increased risk of the development of GDM in
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Chinese women and offer the potential to target women for interventions designed to lower their risk of developing GDM. REFERENCES 1. HAPO Study Cooperative Research Group, Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, et al. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 2008;358: 1991–2002. 2. Tu WJ, Zeng XW, Deng A, Zhao SJ, Luo DZ, Ma GZ, et al. Circulating FABP4 (fatty acid-binding protein 4) is a novel prognostic biomarker in patients with acute ischemic stroke. Stroke 2017;48:1531–8. 3. Xu A, Wang Y, Xu JY, Stejskal D, Tam S, Zhang J, et al. Adipocyte fatty acid–binding protein is a plasma biomarker closely associated with obesity and metabolic syndrome. Clin Chem 2006;52:405–13. 4. Terra X, Quintero Y, Auguet T, Porras JA, Hernández M, Sabench F, et al. FABP 4 is associated with inflammatory markers and metabolic syndrome in morbidly obese women. Eur J Endocrinol 2011;164:539–47. 5. Yeung DC, Xu A, Cheung CW, Wat NM, Yau MH, Fong CH, et al. Serum adipocyte fatty acid-binding protein levels were independently associated with carotid atherosclerosis. Arteriosclerosis Thromb Vasc Biol 2007;27:1796–802. 6. Scifres CM, Catov JM, Simhan H. Maternal serum fatty acid binding protein 4 (FABP4) and the development of preeclampsia. J Clin Endocrinol Metab 2012;97:E349–56. 7. Kralisch S, Klöting N, Ebert T, Kern M, Hoffmann A, Krause K, et al. Circulating adipocyte fatty acid-binding protein induces insulin resistance in mice in vivo. Obesity (Silver Spring) 2015;23:1007–13. 8. Zhang Y, Zhang H, Lu J, Zheng SY, Long T, Li YT, et al. Changes in serum adipocyte fatty acid-binding protein in women with gestational diabetes mellitus and normal pregnant women during mid- and late pregnancy. J Diabetes Investig 2016;7:797–804. 9. Tso AW, Xu A, Sham PC, Wat NM, Wang Y, Fong CH, et al. Serum adipocyte fatty acid-binding protein as a new biomarker predicting the development of type 2 diabetes: a 10-year prospective study in a Chinese cohort. Diabetes Care 2007;30:2667–72. 10. Qiu C, Sorensen TK, Luthy DA, Williams MA. A prospective study of maternal serum C-reactive protein (CRP) concentrations and risk of gestational diabetes mellitus. Paediatr Perinat Epidemiol 2004;18:377–84.
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11. Zhu W, Yang H, Wei Y, Yan J, Wang ZL, Li XL, et al. Evaluation of the value of fasting plasma glucose in the first prenatal visit to diagnose gestational diabetes mellitus in China. Diabetes Care 2013;36:586–90. 12. Pencina MJ, D’Agostino RB Sr, D’Agostino RB Jr, Vasan RS. Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med 2008;27:157–72. 13. Li YY, Xiao R, Li CP, Huangfu J, Mao JF. Increased plasma levels of FABP4 and PTEN is associated with more severe insulin resistance in women with gestational diabetes mellitus. Med Sci Monit 2015;21:426–31. 14. Ortega-Senovilla H, Schaefer-Graf U, Meitzner K, Abou-Dakn M, Graf K, Kintscher U, et al. Gestational diabetes mellitus causes changes in the concentrations of adipocyte fatty acidbinding protein and other adipocytokines in cord blood. Diabetes Care 2011;34:2061–6. 15. Ning H, Tao H, Weng Z, Zhao X. Plasma fatty acid-binding protein 4 (FABP4) as a novel biomarker to predict gestational diabetes mellitus. Acta Diabetol 2016;53:891–8. 16. Chu SY, Callaghan WM, Kim SY, Schmid CH, Lau J, England LJ, et al. Maternal obesity and risk of gestational diabetes mellitus. Diabetes Care 2007;30:2070–6. 17. Bossick AS, Peters RM, Burmeister C, Kakumanu N, Shill JE, Cassidy-Bushrow AE. Antenatal inflammation and gestational diabetes mellitus risk among pregnant African-American women. J Reprod Immunol 2016;115:1–5. 18. Ben-Haroush A, Yogev Y, Hod M. Epidemiology of gestational diabetes mellitus and its association with type 2 diabetes. Diabet Med 2004;21:103–13.
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19. Kim SY, Sappenfield W, Sharma AJ, Wilson HG, Bish CL, Salihu HM, et al. Racial/ethnic differences in the prevalence of gestational diabetes mellitus and maternal overweight and obesity, by nativity, Florida, 2004-2007. Obesity (Silver Spring) 2013;21:E33–40. 20. Biron-Shental T, Schaiff WT, Ratajczak CK, Bildirici I, Nelson DM, Sadovsky Y. Hypoxia regulates the expression of fatty acid-binding proteins in primary term human trophoblasts. Am J Obstet Gynecol 2007;197:516.e1–6. 21. Makkar A, Mishima T, Chang G, Scifres C, Sadovsky Y. Fatty acid binding protein-4 is expressed in the mouse placental labyrinth, yet is dispensable for placental triglyceride accumulation and fetal growth. Placenta 2014;35: 802–7. 22. Baar RA, Dinfelder CS, Smith LA, Bernlohr DA, Wu C, Lange AJ, et al. Investigation of in vivo fatty acid metabolism in AFABP/ap2(-/-) mice. Am J Physiol Endocrinol Metab 2005; 288:E187–93. 23. Coe NR, Bernlohr DA. Physiological properties and functions of intracellular fatty acid-binding proteins. Biochim Biophys Acta 1998;1391:287–306. 24. Maeda K, Cao H, Kono K, Gorgun CZ, Furuhashi M, Uysal KT, et al. Adipocyte/macrophage fatty acid binding proteins control integrated metabolic responses in obesity and diabetes. Cell Metab 2005;1:107–19. 25. Tuncman G, Erbay E, Hom X, De Vivo I, Campos H, Rimm EB, et al. Agenetic variant at the fatty acid-binding protein aP2 locus reduces the risk for hypertriglyceridemia, type 2 diabetes, and cardiovascular disease. Proc Natl Acad Sci U S A 2006;103: 6970–5.
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