妊娠期多种重金属暴露与妊娠期糖尿病风险及葡萄糖刺激后胰岛素分泌期的关系

DOI：10.1016/j.envres.2024.118237

Abstract

BACKGROUND: Epidemiological evidence for the association between heavy metals exposure during pregnancy and gestational diabetes mellitus (GDM) is still inconsistent. Additionally, that is poorly understood about the potential cause behind the association, for instance, whether heavy metal exposure is related to the change of insulin secretion phase is unknown.

 OBJECTIVES: We aimed to explore the relationships of blood levels of arsenic (As), lead (Pb), thallium (Tl), nickel (Ni), cadmium (Cd), cobalt (Co), barium (Ba), chromium (Cr), mercury (Hg) and copper (Cu) during early pregnancy with the odds of GDM, either as an individual or a mixture, as well as the association of the metals with insulin secretion phase after glucose stimulation.

METHODS: We performed a nested case-control study consisting of 302 pregnant women with GDM and 302 controls at the First Affiliated Hospital of Anhui Medical University in Hefei, China. Around the 12th week of pregnancy, blood samples of pregnant women were collected and levels of As, Pb, Tl, Ni, Cd, Co, Ba, Cr, Hg and Cu in blood were measured. An oral glucose tolerance test (OGTT) was done in each pregnant woman during the 24-28th week of pregnancy to diagnose GDM and C-peptide (CP) levels during OGTT were measured simultaneously. The four metals (As, Pb, Tl and Ni) with the highest effect on odds of GDM were selected for the subsequent analyses via the random forest model. Conditional logistic regression models were performed to analyze the relationships of blood As, Pb, Tl and Ni levels with the odds of GDM. The weighted quantile sum (WQS) regression and bayesian kernel machine regression (BKMR) were used to assess the joint effects of levels of As, Pb, Tl and Ni on the odds of GDM as well as to evaluate which metal level contributed most to the association. Latent profile analysis (LPA) was conducted to identify profiles of glycemic and C-peptide levels at different time points. Multiple linear regression models were employed to explore the relationships of metals with glycaemia-related indices (fasting blood glucose (FBG), 1-hour blood glucose (1h BG), 2-hour blood glucose (2h BG), fasting C-peptide (FCP), 1-hour C-peptide (1h CP), 2-hour C-peptide (2h CP), FCP/FBG, 1h CP/1h BG, 2h CP/2h BG, area under the curve of C-peptide (AUCP), area under the curve of glucose (AUCG)), AUCP/AUCG and profiles of BGs and CPs, respectively. Mixed-effects models with repeated measures data were used to explore the relationship between As (the ultimately selected metal) level and glucose-stimulated insulin secretion phase. The mediation effects of AUCP and AUCG on the association of As exposure with odds of GDM were investigated using mediation models.

RESULTS: The odds of GDM in pregnant women increased with every ln unit increase in blood As concentration (OR = 1.46, 95% CI = 1.04-2.05). The joint effects of As, Pb, Tl and Ni levels on the odds of GDM was statistically significant when blood levels of four metals were exceeded their 50th percentile, with As level being a major contributor. Blood As level was positively associated with AUCG and the category of glucose latent profile, the values of AUCG were much higher in GDM group than those in non-GDM group, which suggested that As exposure associated with the odds of GDM may be due to that As exposure was related to the impairment of glucose tolerance among pregnant women. The significant and positive relationships of As level with AUCP, CP latent profile category, 2h CP and 2h CP/2h BG were observed, respectively; and the values of 1h CP/1h BG and AUCP/AUCG were much lower in GDM group than those in non-GDM group, which suggested that As exposure may not relate to the impairment of insulin secretion (pancreatic beta-cell function) among pregnant women. The relationships between As level and 2h CP as well as 2h CP/2h BG were positive and significant; additionally, the values of 2h CP/2h BG in GDM group were comparable with those in non-GDM group; the peak value of CP occurred at 2h in GDM group, as well as the values of 2h CP/2h BG in high As exposure group were much higher than those in low As exposure group, which suggested that As exposure associated with the increased odds of GDM may be due to that As exposure was related to the change of insulin secretion phase (delayment of the peak of insulin secretion) among pregnant women. In addition, AUCP mediated 11% (p < 0.05) and AUCG mediated 43% (p < 0.05) of the association between As exposure and the odds of GDM.

CONCLUSION: Our results suggested that joint exposure to As, Pb, Tl and Ni during early pregnancy was positively associated with the odds of GDM, As was a major contributor; and the association of environmental As exposure with the increased odds of GDM may be due to that As exposure was related to the impairment of glucose tolerance and change of insulin secretion phase after glucose stimulation (delayment of the peak of insulin secretion) among pregnant women.

摘要

背景: 妊娠期重金属暴露与妊娠期糖尿病(GDM)之间关系的流行病学证据仍不一致。此外，人们对这种关联背后的潜在原因知之甚少，例如，重金属暴露是否与胰岛素分泌期的改变有关尚不清楚。

目的: 我们旨在探讨妊娠早期血中砷(As)、铅(Pb)、铊(Tl)、镍(Ni)、镉(Cd)、钴(Co)、钡(Ba)、铬(Cr)、汞(Hg)和铜(Cu)水平与GDM发生率的关系，无论是个体还是混合，以及这些金属与葡萄糖刺激后胰岛素分泌期的关系。

方法: 我们在中国合肥安徽医科大学第一附属医院进行了一项巢式病例对照研究，包括302名GDM孕妇和302名对照组。妊娠第12周前后采集孕妇血样，测定血中As、Pb、Tl、Ni、Cd、Co、Ba、Cr、Hg、Cu的含量。在妊娠24-28周期间，对所有孕妇进行口服葡萄糖耐量试验(OGTT)诊断GDM，同时测定OGTT期间c肽(CP)水平。通过随机森林模型选择对GDM几率影响最大的四种金属(As、Pb、Tl和Ni)进行后续分析。采用条件logistic回归模型分析血中As、Pb、Tl、Ni水平与GDM发病几率的关系。采用加权分位数和(WQS)回归和贝叶斯核机回归(BKMR)来评估砷、铅、硫和镍水平对GDM几率的联合影响，并评估哪种金属水平对GDM的关联贡献最大。采用潜在剖面分析(LPA)确定不同时间点的血糖和c肽水平。采用多元线性回归模型探讨金属与血糖相关指标(空腹血糖(FBG)、1小时血糖(1h BG)、2小时血糖(2h BG)、空腹c肽(FCP)、1小时c肽(1h CP)、2小时c肽(2h CP)、FCP/FBG、1h CP/1h BG、2h CP/2h BG、c肽曲线下面积(AUCP)、葡萄糖曲线下面积(AUCG)、AUCP/AUCG、BGs和CPs谱)的关系。使用重复测量数据的混合效应模型来探索As(最终选择的金属)水平与葡萄糖刺激的胰岛素分泌期之间的关系。采用中介模型探讨了AUCP和AUCG在砷暴露与GDM几率之间的中介作用。

结果: 孕妇发生GDM的几率随血中As浓度每增加ln单位而增加(OR = 1.46,95% CI = 1.04-2.05)。As、Pb、Tl和Ni水平对GDM的共同影响在血液中四种金属水平超过其第50百分位数时具有统计学意义，其中As水平是主要影响因素。血中As水平与AUCG和葡萄糖潜伏谱类别呈正相关，GDM组AUCG值远高于非GDM组，提示与GDM发生率相关的As暴露可能与孕妇糖耐量受损有关。As水平分别与AUCP、CP潜剖面类别、2h CP和2h CP/2h BG呈显著正相关;GDM组1h CP/1h BG和AUCP/AUCG值明显低于非GDM组，提示As暴露可能与孕妇胰岛素分泌(胰腺β细胞功能)受损无关。As水平与2h CP、2h CP/2h BG呈显著正相关;此外，GDM组2h CP/2h BG值与非GDM组相当;GDM组CP峰值出现在2h，高砷暴露组2h CP/2h BG值远高于低砷暴露组，提示与GDM发生率增加相关的砷暴露可能与孕妇胰岛素分泌期的改变(胰岛素分泌高峰的延迟)有关。此外，AUCP介导了11% (p < 0.05)和43% (p < 0.05)的砷暴露与GDM几率之间的关联。

结论: 我们的研究结果表明，妊娠早期联合暴露于砷、铅、硫和镍与GDM的几率呈正相关，砷是主要因素;环境砷暴露与GDM发病几率增加的关系可能是由于砷暴露与孕妇糖耐量的损害和葡萄糖刺激后胰岛素分泌阶段的改变(胰岛素分泌高峰的延迟)有关。