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中华妇幼临床医学杂志(电子版) ›› 2018, Vol. 14 ›› Issue (06) : 636 -643. doi: 10.3877/cma.j.issn.1673-5250.2018.06.003

所属专题： 文献；

论著

血浆CMPF水平诊断妊娠期糖尿病的临床价值
张烨1, 郭晓蒙1, 陶敏芳1, 滕银成1, 顾京红1, 黄亚娟1, 李明1, 蒋荣珍1,†()   
  1. 1. 200233　上海交通大学附属第六人民医院
  • 收稿日期:2018-09-01 修回日期:2018-11-15 出版日期:2018-12-01
  • 通信作者: 蒋荣珍

Clinical values of plasma CMPF level in diagnosis of gestational diabetes mellitus

Ye Zhang1, Xiaomeng Guo1, Minfang Tao1, Yincheng Teng1, Jinghong Gu1, Yajuan Huang1, Ming Li1, Rongzhen Jiang1,†()   

  1. 1. Sixth People′s Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200233, China
  • Received:2018-09-01 Revised:2018-11-15 Published:2018-12-01
  • Corresponding author: Rongzhen Jiang
  • About author:
    Corresponding author: Jiang Rongzhen, Email:
  • Supported by:
    National Natural Science Foundation of China(81570444); Key Discipline Construction Project in the Fourth Round of Public Health Action Plan of Shanghai(15GWZK0701); Project of Science and Technology Innovation Action Plan of Shanghai(17411950602)
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引用本文：

张烨, 郭晓蒙, 陶敏芳, 滕银成, 顾京红, 黄亚娟, 李明, 蒋荣珍. 血浆CMPF水平诊断妊娠期糖尿病的临床价值[J]. 中华妇幼临床医学杂志(电子版), 2018, 14(06): 636-643.

Ye Zhang, Xiaomeng Guo, Minfang Tao, Yincheng Teng, Jinghong Gu, Yajuan Huang, Ming Li, Rongzhen Jiang. Clinical values of plasma CMPF level in diagnosis of gestational diabetes mellitus[J]. Chinese Journal of Obstetrics & Gynecology and Pediatrics(Electronic Edition), 2018, 14(06): 636-643.

目的

探讨血浆3-羧基-4-甲基-5-丙基-2-呋喃丙酸(CMPF)水平诊断妊娠期糖尿病(GDM)的临床价值。

方法

选取2016年1月至2017年6月，于上海交通大学附属第六人民医院就诊的60例孕妇为研究对象，按照是否合并GDM，将其分为GDM组(n＝ 40)和对照组(n＝20)。所有孕妇于中孕期(孕龄为13～18孕周)，进行生化指标检测；于孕龄为24～28孕周时，进行口服葡萄糖耐量试验(OGTT)检查，同时利用超高效液相色谱-三重四极杆质谱联用技术，检测孕妇血浆CMPF水平。采用成组t检验，对2组孕妇孕龄为28孕周及新生儿足月时人体质量指数(BMI)，以及高密度脂蛋白(HDL)、低密度脂蛋白(LDL)、总蛋白、白蛋白、尿素、尿酸水平等指标进行比较。采用Mann-Whitney U检验，对2组孕妇的孕龄、孕次、产次、血浆CMPF水平、孕龄为18孕周时BMI及糖化血红蛋白(HbA1c)、糖化白蛋白(GA)、肌酐水平等指标进行比较。采用多因素非条件logistic回归分析，对孕妇发生GDM的影响因素进行分析。绘制血浆CMPF水平及孕龄为18、28孕周时BMI诊断GDM的受试者工作特征(ROC)曲线，以及这3个指标联合诊断与OGTT 0、1、2 h血糖浓度联合诊断GDM的ROC，并计算ROC曲线下面积(ROC-AUC)。本研究遵循的程序符合上海交通大学附属第六人民医院人体试验委员会制定的伦理学标准，并经过该伦理委员会批准(审批文号：2017-012)，分组征得2组受试者知情同意，并与之签署临床研究知情同意书。

结果

①2组孕妇的孕龄、孕次和产次等一般临床资料比较，差异均无统计学意义(P>0.05)。②GDM组血浆CMPF值为522.0 ng/mL(326.9～989.3 ng/mL)，显著高于对照组的280.2 ng/mL(177.8～466.6 ng/mL)，2组比较，差异有统计学意义(U＝576.000，P＝0.006)。③GDM组孕妇孕龄为18、28孕周及新生儿足月时BMI与HbA1c分别为24.6 kg/m2 (22.0～25.9 kg/m2)、(26.1±2.8) kg/m2、(27.6±2.9) kg/m2、5.4%(5.3%～5.6%)，均显著高于对照组的22.8 kg/m2 (20.1～23.6 kg/m2)、(24.5±2.6) kg/m2、(25.5±2.6) kg/m2、5.2%(5.0%～5.3%)，并且差异均有统计学意义(U＝568.000，P＝0.002；t＝2.150，P＝0.001；t＝1.180，P＝0.036；U＝226.000，P<0.001)。GDM组孕妇GA值为11.6%(10.8%～12.8%)，低于对照组的12.6%(12.2%～13.2%)，并且差异亦有统计学意义(U＝248.000，P＝0.017)。④对孕妇发生GDM影响因素进行多因素非条件logistic回归分析的结果显示，血浆CMPF水平及孕龄为18、28孕周时BMI，均为孕妇发生GDM的独立影响因素(OR＝1.003，95%CI：1.000～1.005，P＝0.023；OR＝4.393，95%CI：1.675～11.525，P＝0.003；OR＝0.322，95%CI：0.130～0.798，P＝0.014)。⑤通过ROC曲线分析结果显示，血浆CMPF水平及孕龄为18、28孕周时BMI诊断GDM的ROC-AUC分别为0.703(95%CI：0.554～0.852，P＝0.014)，0.741(95%CI：0.605～0.876，P＝0.004)及0.672(95%CI：0.523～0.821，P＝0.039)。这3个指标联合诊断GDM的ROC-AUC为0.847(95%CI：0.741～0.952，P<0.001)，与OGTT 0、1、2 h血糖浓度联合诊断GDM的ROC-AUC[0.983(95%CI：0.957～1.000，P<0.001)]比较，差异无统计学意义(U＝9.000，P＝0.100)。根据约登指数最大原则，血浆CMPF水平及孕龄为18、28孕周时BMI诊断GDM的最佳临界值分别为397.2 ng/mL、23.9 kg/m2、26.2 kg/m2，此时其诊断GDM的敏感度分别为65.6%、59.4%、53.1%，特异度分别为75.0%、90.0%、80.0%。

结论

GDM孕妇孕龄为24～28孕周时血浆CMPF水平联合孕龄为18、28孕周时BMI，对GDM诊断具有较好临床价值。

关键词: 3-羧基-4-甲基-5-丙基-2-呋喃丙酸, 糖尿病，妊娠, 人体质量指数, 诊断, Logistic模型, ROC曲线, 孕妇
Objective

To investigate clinical values of plasma 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) level in diagnosis of gestational diabetes mellitus (GDM).

Methods

A total of 60 pregnant women who admitted into Sixth People′s Hospital Affiliated to Shanghai Jiao Tong University from January 2016 to June 2017 were selected as the study subjects. They were divided into GDM group (n=40) and control group (n=20) according to whether they were combined with GDM or not. All pregnant women were tested for biochemical markers during 13 to 18 gestational weeks. And 75 g oral glucose tolerance test (OGTT) was performed during 24 to 28 gestational weeks. At the same time, ultra-high performance liquid chromatography-triple quadrupole mass spectrometry was used to detect plasma CMPF level. The body mass index (BMI) at 28 gestational weeks and at neonatal term, high-density lipoprotein (HDL), low-density lipoprotein (LDL), total protein, albumin, urea, and uric acid were compared between two groups by independent-samples t test. Gestational age, gravidity, parity, plasma CMPF level, BMI at 18 gestational weeks, hemoglobin A1c (HbA1c), glycated albumin (GA), creatinine and other indicators between two groups were compared by Mann-Whitney U test. Multiple unconditional logistic regression analysis was used to analyze the influencing factors of GDM in pregnant women. The receiver operating characteristics (ROC) curves for plasma CMPF level and BMI at 18, 28 gestational weeks, and the combination these 3 factors, and the combination of OGTT 0, 1, 2 h blood glucose concentrations in diagnosis of GDM were built respectively, and the area under ROC curve (ROC-AUC) of them were calculated. The procedures followed in this study were in accordance with the ethical standards established by the Human Subjects Trial Committee of the Sixth People′s Hospital Affiliated to Shanghai Jiao Tong University, and this study was approved by this committee (approval number: 2017-012). Informed consent was obtained and signed with each subject.

Results

① There was no significant difference in the general clinical data such as gestational age, gravidity and parity between two groups (P>0.05). ②The plasma CMPF level of GDM group was 522.0 ng/mL (326.9-989.3 ng/mL), which was significantly higher than that of control group 280.2 ng/mL (177.8-466.6 ng/mL). The difference between two groups was statistically significant (U=576.000, P=0.006). ③BMI at 18, 28 gestational weeks and at neonatal term, and HbA1c in GDM group were 24.6 kg/m2 (22.0-25.9 kg/m2), (26.1±2.8) kg/m2, (27.6±2.9) kg/m2, and 5.4% (5.3%-5.6%), respectively, which were significantly higher than those in control group 22.8 kg/m2 (20.1-23.6 kg/m2), (24.5±2.6) kg/m2, (25.5±2.6) kg/m2, 5.2% (5.0%-5.3%), and all the differences were statistically significant (U=568.000, P=0.002; t=2.150, P=0.001; t=1.180, P=0.036; U=226.000, P<0.001). The GA in GDM group was 11.6% (10.8%-12.8%), which was significantly lower than that in control group 12.6% (12.2%-13.2%), and the difference was also statistically significant (U=248.000, P=0.017). ④The results of multiple unconditional logistic regression analysis of the influencing factors of GDM in pregnant women showed that plasma CMPF levels and BMI at 18, 28 gestational weeks were independent influencing factors of GDM in pregnant women (OR=1.003, 95%CI: 1.000-1.005, P=0.023; OR=4.393, 95%CI: 1.675-11.525, P=0.003; OR=0.322, 95%CI: 0.130-0.798, P=0.014). ⑤The results of ROC curve analysis showed that the ROC-AUC of plasma CMPF level, BMI at 18, 28 gestational weeks in diagnosis of GDM were 0.703 (95%CI: 0.554-0.852, P=0.014), 0.741 (95%CI: 0.605-0.876, P=0.004), and 0.672 (95%CI: 0.523-0.821, P=0.039), respectively. The ROC-AUC of plasma CMPF level combined with BMI at 18 and 28 gestational weeks in diagnosis of GDM was 0.847 (95%CI: 0.741-0.952, P<0.001), and the ROC-AUC of combination of OGTT 0, 1, 2 h blood glucose concentrations in diagnosis of GDM was 0.983 (95%CI: 0.957-1.000, P<0.001), and there was no statistically significant difference between them (U=9.000, P=0.100). According to the maximum principle of Youden index, the best cut-off values of plasma CMPF level and BMI at 18, 28 gestational weeks for diagnosis of GDM were 397.2 ng/mL, 23.9 kg/m2, 26.2 kg/m2, respectively, and the sensitivities of them in diagnosis of GDM were 65.6%, 59.4% and 53.1%, respectively, and the specificities were 75.0%, 90.0% and 80.0%, respectively.

Conclusion

The plasma CMPF level at 24 to 28 gestational weeks combined with BMI at 18 and 28 gestational weeks has a good clinical diagnostic value for GDM.

Key words: 3-Carboxy-4-methyl-5-propyl-2-furanpropanoic acid, Diabetes, gestational, Body mass index, Diagnosis, Logistic models, ROC curve, Pregnant women
表1 2组孕妇的一般临床资料比较
组别 例数 孕龄[周，M(P25～P75)] 孕次[次，M(P25～P75)] 产次[次，M(P25～P75)]
GDM组对照组 4020 27.1(25.4～28.1)25.2(24.2～27.1) 2(1～3)1(1～2) 0(0～1)0(0～1)
U值 ? 405.500 502.000 430.000
P值 ? 0.931 0.090 0.553
图1 2组孕妇血浆CMPF水平柱状图及统计学比较
表2 2组孕妇不同时间点BMI和中孕期生化指标比较
组别 例数 BMI (kg/m2) HbA1c[%，M(P25～P75)]
孕前[M(P25～P75)] 孕龄为18孕周时[M(P25～P75)] 孕龄为28孕周时(±s) 新生儿足月时(±s)
GDM组 40 23.0(20.6～24.9) 24.6(22.0～25.9) 26.1±2.8 27.6±2.9 5.4(5.3～5.6)
对照组 20 21.8(19.4～23.2) 22.8(20.1～23.6) 24.5±2.6 25.5±2.6 5.2(5.0～5.3)
检验值 ? U＝492.000 U＝568.000 t＝2.150 t＝1.810 U＝226.000
P值 ? 0.149 0.002 0.001 0.036 <0.001
组别 例数 GA[%，M(P25～P75)] TD(mmol/L，±s) TC(mmol/L，±s) HDL(mmol/L，±s) LDL(mmol/L，±s)
GDM组 40 11.6(10.8～12.8) 4.7±0.8 1.7±0.8 1.7±0.4 2.4±0.6
对照组 20 12.6(12.2～13.2) 4.5±0.7 1.6±0.6 1.7±0.4 2.2±0.4
检验值 ? U＝248.000 t＝0.913 t＝0.625 t＝0.309 t＝0.656
P值 ? 0.017 0.365 0.535 0.758 0.515
组别 例数 总蛋白(g/L，±s) 白蛋白(g/L，±s) 尿素(mmol/L，±s) 肌酐[mmol/L，M(P25～P75)] 尿酸(mmol/L，±s)
GDM组 40 68.2±3.4 43.8±3.1 2.9±0.8 43.0(39.0～47.0) 203.8±43.0
对照组 20 67.8±3.4 43.9±2.7 3.1±0.7 41.0(37.5～47.8) 201.4±42.1
检验值 ? t＝0.882 t＝0.180 t＝0.970 U＝201.500 t＝0.209
P值 ? 0.382 0.858 0.335 0.384 0.835
表3 孕妇发生GDM影响因素的多因素非条件logistic回归分析的变量含义及其赋值情况
自变量/因变量 变量名 赋值
是否发生GDM y y＝0表示未发生GDM；y＝1表示发生GDM
血浆CMPF水平 x1 为定量变量(ng/mL)
孕龄为18孕周时BMI x2 为定量变量(kg/m2)
孕龄为28孕周时BMI x3 为定量变量(kg/m2)
年龄 x4 为定量变量(岁)
孕前BMI x5 为定量变量(kg/m2)
TD浓度 x6 为定量变量(mmol/L)
TC浓度 x7 为定量变量(mmol/L)
HDL浓度 x8 为定量变量(mmol/L)
LDL浓度 x9 为定量变量(mmol/L)
表4 孕妇发生GDM影响因素的多因素非条件logistic回归分析结果
影响因素 B SE Wald值 P值 OR值 OR值95%CI
常数项血浆CMPF水平 －6.2990.003 3.7640.001 2.8015.146 0.0940.023 0.0021.003 —1.000～1.005
孕龄为18孕周时BMI 1.480 0.492 9.047 0.003 4.393 1.675～11.525
孕龄为28孕周时BMI －1.132 0.462 5.997 0.014 0.322 0.130～0.798
图2 不同指标诊断GDM的ROC曲线
表5 不同指标诊断GDM的ROC-AUC
诊断指标 ROC-AUC P值 ROC-AUC 95%CI
血浆CMPF水平 0.703 0.014 0.554～0.852
孕龄为18孕周时BMI 0.741 0.004 0.605～0.876
孕龄为28孕周时BMI 0.672 0.039 0.523～0.821
血浆CMPF水平联合孕龄为18及28孕周时BMI 0.847 <0.001 0.741～0.952
OGTT 0 h血糖浓度 0.896 <0.001 0.809～0.983
OGTT 1 h血糖浓度 0.920 <0.001 0.845～0.996
OGTT 2 h血糖浓度 0.889 <0.001 0.803～0.975
OGTT 0、1、2 h血糖浓度 0.983 <0.001 0.957～1.000
表6 约登指数最大时，血浆CMPF水平及孕龄为18、28孕周时BMI诊断GDM的价值分析结果
诊断指标 最佳临界值 敏感度(%) 特异度(%) 约登指数
血浆CMPF水平 397.2 ng/mL 65.6 75.0 0.406
孕龄为18孕周时BMI 23.9 kg/m2 59.4 90.0 0.494
孕龄为28孕周时BMI 26.2 kg/m2 53.1 80.0 0.331
[1]
谢幸，苟文丽．妇产科学[M].8版．北京：人民卫生出版社，2013.
[2]
Zhu WW, Yang HX, Wang C, et al. High prevalence of gestational diabetes mellitus in Beijing: effect of maternal birth weight and other risk factors[J]. Chin Med J, 2017, 130(9): 1019-1025.
[3]
Wei Y, Yang H, Zhu W, et al. International Association of Diabetes and Pregnancy Study Group criteria is suitable for gestational diabetes mellitus diagnosis: further evidence from China[J]. Chin Med J, 2014, 127(20):3553-3556.
[4]
宋耕，薛聪颖，杨慧霞. 妊娠期糖尿病再妊娠复发的预测与预防[J]. 中国实用内科杂志，2018，38(6):538-540.
[5]
Schwartz N, Nachum Z, Green MS. The prevalence of gestational diabetes mellitus recurrence: effect of ethnicity and parity: a Meta analysis[J]. Am J Obstet Gynecol, 2015, 213(3): 310-317.
[6]
姜艳，李光辉，刘晓巍. 孕妇年龄及孕早期空腹血糖水平在预测妊娠期糖尿病发病中的临床价值研究[J]. 中国实用妇科与产科杂志，2018, 34(2): 176-180.
[7]
Prentice KJ, Luu L, Allister EM, et al. The furan fatty acid metabolite CMPF is elevated in diabetes and induces β cell dysfunction [J]. Cell Metab, 2014, 19(4): 653-666.
[8]
Liu Y, Prentice KJ, Eversley JA, et al. Rapid elevation in CMPF may act as a tipping point in diabetes development [J]. Cell Rep, 2016, 14(12): 2889-2900.
[9]
Retnakaran R, Ye C, Kramer CK, et al. Evaluation of circulating determinants of beta-cell function in women with and without gestational diabetes [J]. J Clin Endocrinol Metab, 2016, 101(7): 2683-2691.
[10]
Shepherd E, Gomersall JC, Tieu J, et al. Combined diet and exercise interventions for preventing gestational diabetes mellitus [J]. Cochrane Database Syst Rev, 2017, 11: CD010443.
[11]
Song C, Li J, Leng J, et al. Lifestyle intervention can reduce the risk of gestational diabetes: a Meta-analysis of randomized controlled trials[J]. Obes Rev, 2016, 17(10): 960-969.
[12]
Guelfi KJ, Ong MJ, Crisp NA, et al. Regular exercise to prevent the recurrence of gestational diabetes mellitus: a randomized controlled trial[J]. Obstet Gynecol, 2016, 128(4): 819-827.
[13]
Wahl HG, Tetschner B, Liebich HM. The effect of dietary fish oil supplementation on the concentration of 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid in human blood and urine[J]. J Separat Sci, 2015, 15(12): 815-818.
[14]
Hanhineva K, Lankinen MA, Pedret A, et al. Nontargeted metabolite profiling discriminates diet-specific biomarkers for consumption of whole grains, fatty fish, and bilberries in a randomized controlled trial [J]. J Nutr, 2015, 145(1): 7-17.
[15]
Ansorg R, Bickenbach R, Weber R, et al. Fluorescence serological differentiation between somatic and flagellar antigens of Pseudomonas aeruginosa [J]. Z Allg Mikrobiol, 1977, 17(3): 243-247.
[16]
Holt HM, Gahrn-Hansen B, Bruun B. Shewanella algae and Shewanella putrefaciens: clinical and microbiological characteristics [J]. Clin Microbiol Infect, 2005, 11(5): 347-352.
[17]
Xu L, Sinclair AJ, Faiza M, et al. Furan fatty acids: beneficial or harmful to health? [J]. Prog Lipid Res, 2017, 68: 119-137.
[18]
Miyamoto Y, Iwao Y, Mera K, et al. A uremic toxin, 3-carboxy-4-methyl-5-propyl-2-furanpropionate induces cell damage to proximal tubular cells via the generation of a radical intermediate [J]. Biochem Pharmacol, 2012, 84(9): 1207-1214.
[19]
Yi J, Jin H, Zhang R, et al. Increased serum 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) levels are associated with glucose metabolism in Chinese pregnant women [J]. J Endocrinol Invest, 2018, 41(6): 663-670.
[20]
葛均波，徐永健. 内科学[M]. 8版. 北京：人民卫生出版社，2014.
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