Liver biomarkers, lipid metabolites, and risk of gestational diabetes mellitus in a prospective study among Chinese pregnant women

Abstract

Background: Liver plays an important role in maintaining glucose homeostasis. We aimed to examine the associations of liver enzymes and hepatic steatosis index (HSI, a reliable biomarker for non-alcoholic fatty liver disease) in early pregnancy with subsequent GDM risk, as well as the potential mediation effects of lipid metabolites on the association between HSI and GDM.

Methods: In a birth cohort, liver enzymes were measured in early pregnancy (6-15 gestational weeks, mean 10) among 6,860 Chinese women. Multivariable logistic regression was performed to examine the association between liver biomarkers and risk of GDM. Pearson partial correlation and least absolute shrinkage and selection operator (LASSO) regression were conducted to identify lipid metabolites that were significantly associated with HSI in a subset of 948 women. Mediation analyses were performed to estimate the mediating roles of lipid metabolites on the association of HSI with GDM.

Results: Liver enzymes and HSI were associated with higher risks of GDM after adjustment for potential confounders, with ORs ranging from 1.42 to 2.24 for extreme-quartile comparisons (false discovery rate-adjusted P-trend ≤0.005). On the natural log scale, each SD increment of alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, and HSI was associated with a 1.15-fold (95% CI: 1.05, 1.26), 1.10-fold (1.01, 1.20), 1.21-fold (1.10, 1.32), 1.15-fold (1.04, 1.27), and 1.33-fold (1.18, 1.51) increased risk of GDM, respectively. Pearson partial correlation and LASSO regression identified 15 specific lipid metabolites in relation to HSI. Up to 52.6% of the association between HSI and GDM risk was attributed to the indirect effect of the HSI-related lipid score composed of lipid metabolites predominantly from phospholipids (e.g., lysophosphatidylcholine and ceramides) and triacylglycerol.

Conclusions: Elevated liver enzymes and HSI in early pregnancy, even within a normal range, were associated with higher risks of GDM among Chinese pregnant women. The association of HSI with GDM was largely mediated by altered lipid metabolism.

Keywords: Birth cohort; Gestational diabetes mellitus; Hepatic steatosis index; Lipidomics; Liver enzyme.

Fig. 1

Pearson partial correlations of 328 lipid metabolites with HSI in Manhattan plot and volcano plot (n=948). A Manhattan plot showed associations of HSI with 328 lipid metabolites according to lipid classes/subclasses. B Volcano plot showed associations of HSI with lipid metabolites according to the significance and partial correlation coefficients. The horizontal dotted line represented the significance threshold (FDR-adjusted P =0.05). The scatter denoted the up-regulated (red) or down-regulated (green) lipids for correlations with HSI. Partial correlations were adjusted for maternal age, gestational age, and GDM status. Abbreviations: GDM, gestational diabetes mellitus; HSI, hepatic steatosis index; BMP, Bis(monoacylglycerol)phosphate; CE, Cholesterol ester; Cer, Ceramide; COH, free cholesterol; DG, Diacylglyceride; DHC, Dihexosyl ceramide; FDR, false discovery rate; LPC, Lysophosphatidylcholine; LPC(O), Lyso alkylphosphatidylcholine; LPE, Lyso phosphatidylethanolamine; MHC, Mono hexosyl ceramide; PC, Phosphatidylcholine; PC(O), Alkylphosphatidylcholine; PC(P), Phosphatidylcholine plasmalogen; PE, Phosphatidylethanolamine; PE(O), Alkylphosphatidylethanolamine; PE(P), Phosphatidylethanolamine plasmalogen; PG, Phosphatidylglycerol; PI, Phosphatidylinositol; PS, Phosphatidylserine; SM, Sphingomyelin; TG, Triacylglycerol

Fig. 2

Forest plots for associations between HSI, lipids, and GDM risk (n=948). Results were expressed as difference (95% CI) of lipid z-score for per SD increment of HSI on the log scale and odds ratio (95% CI) of GDM for per unit increment of lipid z-score. Models were adjusted for maternal age, gestational age, parity, family history of diabetes, history of GDM, pre-pregnancy BMI, systolic blood pressure, smoke status, alcohol drinking status, physical activity, and fasting blood glucose. Pre-pregnancy BMI was treated as a categorical variable (<18.5, 18.5-24.0, and ≥24.0 kg/m²) in the multivariable model for associations between HSI and HSI-related lipids. Proportions of mediation were calculated according to the formula: (indirect effect / total effect on the log scale) × 100%. * Indirect effects were significant according to confidence intervals obtained by bootstrapping approach with 1000 samples. Abbreviations: BMI, body mass index; Cer, ceramide; CI, confidence interval; GDM, gestational diabetes mellitus; HSI, hepatic steatosis index; LPC, lysophosphatidylcholine; LPC(O), lyso alkylphosphatidylcholine; PC, Phosphatidylcholine; PC(O), alkylphosphatidylcholine; PC(P), Phosphatidylcholine plasmalogen; SD, standard deviation; SM, sphingomyelin; TG, triacylglycerol