Serum growth differentiation factor 15 is associated with glucose metabolism in the third trimester in Chinese pregnant women
Introduction
Gestational diabetes mellitus (GDM), a disease defined as abnormal glucose tolerance with onset or first recognition during gestation [1], occurs in approximately 14.8% of all pregnancies in mainland China according to a recent meta-analysis [2]. GDM has been proved to be associated with a variety of complications, including gestational hypertension, cardiovascular disease and cesarean delivery in mothers as well as macrosomia, respiratory distress syndrome and hypoglycemia in neonates [3], [4]. Moreover, GDM patients and their offspring will have a higher risk of type 2 diabetes (T2DM) and obesity in the long term [5]. To date, the pathogenesis of GDM is still unclear, but there is evidence that GDM is analogical to T2DM because of the similarity of the underlying pathophysiology of inadequate beta cell compensation to the increased insulin requirements and a majority of shared susceptibility genes [1], [6].
Growth differentiation factor 15 (GDF15), also known as macrophage inhibitory cytokine-10 (MIC-1), is a distant member of the transforming growth factor β superfamily [7]. GDF15 is expressed in large amounts by placental trophoblasts and can be robustly induced by both acute and chronic inflammatory states, including tissue injury, cancer, cardiovascular disease, nephrosis and diabetes [8], [9], [10], [11]. In recent years, significant associations between GDF15 and glycometabolic disorders have been found in human and animal studies. Temporary high glucose and insulin states could induce the transient increasement of GDF 15 levels [12], [13], and GDF15 overexpressing mice had obviously reduced body weight and glucose intolerance as well as improved insulin sensitivity while an antibody to GDF15 could efficiently reverse these effects [14]. In addition, GDF15 was also demonstrated to play a significant role in regulating lipid levels by these findings that GDF15 levels were negative associated with total cholesterol and transgenic GDF15 overexpressing mice had improved lipid metabolism [9], [15]. These evidences indicated GDF15 might be a protective factor in glucolipid metabolism.
The immune-tolerant state of mothers is important for a healthy pregnancy, so the immunosuppressive function of GDF15 might play a significantly protective role throughout gestation [7], [16]. Study has shown that GDF15 levels were high in the serum of pregnant women, and its level increased substantially with the progression of gestation and peaked in the third trimester [8]. In view of the important role of GDF15 in gestation and glucolipid metabolism, there probably be some relationships between serum GDF15 levels and gestational diseases especially GDM. However, until now, only one study with a small sample size concluded that GDF15 levels in the second trimester were not significantly different between the patients with GDM and the normal controls [17]. Therefore, we aimed to investigate whether serum GDF15 levels in the second and third trimesters were associated with glucose and lipid metabolism parameters.
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Study subjects
Paired by maternal age (±3 years), pregestational BMI (±3 kg/m2), and gestational week (±3 weeks), a total of 330 GDM patients and 330 matched normal controls were recruited from University of Hong Kong Shenzhen Hospital in this study, including 200 GDM patients and 200 matched normal controls in the second trimester as well as 130 GDM patients and 130 matched normal controls in the third trimester. Women with autoimmune disease, thyroid disease, heart trouble, liver or kidney disease, tumors,
Characteristics of subjects
Table 1 shows the clinical characteristics of all participants. In the third trimester, GDM patients were more likely to have higher changes of BMI and higher levels of FBG, 1 h-PG, 2 h-PG, AUCG, HbA1c, and gestational age (all P < 0.05), but lower total cholesterol, triglycerides and delivery gestational age than normal controls (all P < 0.005). In the second trimester, GDM patients also had higher levels of FBG, 1 h-PG, 2 h-PG, AUCG, fasting insulin, HOMA-IR, HbA1c, and HDL-C (all P < 0.05),
Discussion
Although there is emerging evidence from a great number of studies which have proved the important role of GDF15 in glucose and lipid metabolism [12], [15], the clinical relationship between GDF15 and GDM has been seldom researched. In this study, we explored the associations between GDM and serum GDF15 levels and found that concentrations of GDF15 were positively correlated with glucose metabolism in the third trimester.
Serum GDF15 levels have been reported to be high in pregnant women and
Acknowledgments
This work was supported by the National Key Research and Development Project of China (2016YFC1304902), National Science Foundation of China (81570713 and 91649112), Outstanding Academic Leaders of Shanghai Health System (2017BR008), the National Program for Support of Top-notch Young Professionals and Yangtze River Scholar, The University of Hong Kong-Shenzhen Hospital “High-level Hospital” Construction Scientific Research Cultivation Plan (201901025).
Author contributions
CH designed the study. MT performed the experiments, statistical analysis and wrote the manuscript. MT and ML collected and checked the data; WL, SW and RZ helped to perform the experiment. XY and XZ reviewed the manuscript. CH reviewed and revised the manuscript. All authors have read and approved the final manuscript.
Declaration of Competing Interest
The authors have nothing to disclose.
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The two authors contributed equally to this work.