Serum growth differentiation factor 15 is associated with glucose metabolism in the third trimester in Chinese pregnant women

Abstract

Objective

Growth differentiation factor 15 (GDF15) has been demonstrated to increase in diabetes as a protective factor. However, studies assessing relationships between GDF15 levels and gestational diabetes mellitus (GDM) are limited. In this study, we aimed to investigate whether GDF15 levels are related to GDM in Chinese subjects.

Methods

We included 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. Serum GDF15 levels of all participants were determined using an enzyme-linked immunosorbent assay (ELISA). Then, according to GDF15 levels, we equally divided the participants in the second and third trimesters into four subgroups respectively. The relationships of serum GDF15 levels with glucolipid metabolism indicators were analyzed.

Results

In the third trimester, GDF15 levels were significantly higher in the GDM patients than in the normal controls (P < 0.001). Additionally, fasting blood glucose (FBG), 1-h postprandial glucose (1h-PG), 2-h postprandial glucose (2h-PG), hemoglobin A1C (HbA1c) and area under curve of glucose (AUCG) from the 75-g oral glucose tolerance test (OGTT) were positively associated with GDF15 levels (P < 0.05), even after adjusting for age, pregestational BMI, changes of BMI until the third trimester, gestational age, twin and family history of diabetes. Moreover, GDF15 levels were higher in the third trimester than in the second trimester (P < 0.001). No significant relationships were found between GDF15 levels and glucolipid metabolism in the second trimester (P > 0.05).

Conclusions

Serum GDF15 levels were positively correlated 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.