Circulating milk fat globule-epidermal growth factor 8 levels are increased in pregnancy and gestational diabetes mellitus

Abstract

Aims/introduction: Milk fat globule-epidermal growth factor 8 (MFG-E8) is the key mediator in anti-inflammatory responses that facilitate phagocytosis of apoptotic cells, and play an essential role in type 2 diabetes and pregnancy, both of which are under a low-grade inflammatory state. However, the action of MFG-E8 in gestational diabetes mellitus (GDM) is unclear. We measured plasma MFG-E8 levels in pregnancy and GDM for the first time, and elucidated possible relationships between its plasma levels and various metabolic parameters.

Materials and methods: Plasma MFG-E8 levels were quantified by enzyme-linked immunosorbent assay in 66 women with GDM, 70 with normal pregnancy (p-NGT) and 44 healthy non-pregnant controls (CON), who were matched for age and body mass index. Inflammatory factors tumor necrosis factor-α (TNF-α) and C-reactive protein levels were measured, oral glucose tolerance test was carried out and β-cell function was evaluated.

Results: Plasma MFG-E8 levels were remarkably higher in p-NGT than in CON (P = 0.024), and were further elevated in GDM vs p-NGT (P = 0.016). MFG-E8 concentrations correlated positively with hemoglobin A1c, glucose levels and insulin resistance (homeostasis model assessment for insulin resistance), and correlated inversely with TNF-α and insulin secretion evaluated by disposition indices in pregnancies. Fasting glucose levels, disposition index of first phase insulin secretion and TNF-α were independent predictors of MFG-E8 levels in pregnancies. Logistic regression analyses showed that women in the third tertile of MFG-E8 levels had a markedly elevated risk of GDM.

Conclusions: Circulating MFG-E8 levels are dramatically elevated in pregnancy, and are significantly higher in GDM vs p-NGT. MFG-E8 concentrations are significantly associated with TNF-α, fasting glucose levels, homeostasis model assessment for insulin resistance and disposition indices. However, further studies are required to elucidate the regulation mechanism of MFG-E8 during pregnancy and GDM.

Keywords: Gestational diabetes mellitus; Inflammation; Milk-fat globule-epidermal growth factor 8.

Figure 1

Correlation of plasma milk fat globule‐epidermal growth factor 8 (MFG‐E8) levels (log10 transformed) with (a) tumor necrosis factor‐α levels, (b) glycosylated hemoglobin, (c) fasting glucose levels (d) homeostasis model assessment of insulin resistance, log10 transformed (Lg HOMA‐IR), (e) insulin sensitivity index, (f) disposition index of first phase insulin secretion, log10 transformed (Lg DI1st) and (g) disposition index of second phase insulin secretion, log10 transformed (Lg DI2nd). Circles represent normal pregnancy, diamonds represent gestational diabetes mellitus.

Figure 2

Log10 transformed milk fat globule‐epidermal growth factor 8 (LgMFG‐E8) in tertiles of (a) homeostasis model assessment of insulin resistance (HOMA‐IR), (b) Matsuda index, (d) disposition index of first phase insulin secretion (DI _1st) and (d) disposition index of second phase insulin secretion (DI _2nd). Data were shown as mean ± standard error of the men. MFG‐E8 was logarithmically transformed for comparison. Differences between groups were assessed by one‐way ancova adjusted for age, pre‐pregnancy body mass index, systolic blood pressure, diastolic blood pressure, total serum cholesterol and triglyceride. *P < 0.05 vs the first tertile, ^# P < 0.05 vs the second tertile.

Figure 3

Odds of developing gestational diabetes mellitus by milk fat globule‐epidermal growth factor 8 (MFG‐E8) tertiles. Participants were divided into tertiles based on the MFG‐E8 levels. Univariate (white) and multivariate (dark) logistic regression analyses were used to determine odds ratios for the development of gestational diabetes mellitus in each tertile. The multivariate logistic regression model includes adjustment for age, pre‐pregnancy body mass index, systolic blood pressure, diastolic blood pressure, total serum cholesterol and triglyceride. **Significantly different from the reference tertile at the P < 0.01 level.