Introduction
Gestational diabetes mellitus (GDM) is characterized by elevated blood sugar levels first detected during pregnancy. GDM affects approximately 15% of pregnancies worldwide, accounting for approximately 18 million births annually [
1‐
3]. GDM poses various risks to expectant mothers, including prenatal hypertension, pre-eclampsia, premature rupture of membranes, the birth of large-for-gestational-age babies, and an increased likelihood of cesarean section delivery [
1,
4,
5]. Additionally, GDM heightens the chances of complications such as impaired carbohydrate metabolism, obesity, and cardiovascular disease. It also predisposes both the mother and the infant to the development of type 2 diabetes mellitus (T2DM) [
6,
7]. The increased prevalence of GDM incurs significant economic costs, underscoring the need for heightened attention and awareness [
8,
9]. Therefore, gaining an in-depth understanding of the risk factors associated with GDM is crucial.
GDM is influenced by various risk factors, including family history, age, dyslipidemia, obesity, and lack of physical activity [
10,
11]. The relationship between dyslipidemia and GDM is controversial [
12‐
14]. In one study, pregnant women with GDM exhibited higher serum lipid profiles compared to healthy pregnant women, including the ratios of low-density lipid cholesterol to high-density lipoprotein cholesterol (LDL-c/HDL-c ratio) and triglycerides to high-density lipoprotein cholesterol (TG/HDL-c ratio), as well as HDL-c levels [
14]. However, other studies have reported no significant differences in serum levels of high-density lipoprotein cholesterol (HDL-c), total cholesterol (TC), triglycerides (TG), and low-density lipid cholesterol (LDL-c) between pregnant women with and without GDM [
13,
15]. Recently, another marker, namely remnant cholesterol (RC), has been identified as being associated with an increased risk of cardiovascular diseases (CVD) and all-cause mortality [
16,
17]. RC is characterized by lipoprotein cholesterol levels rich in TG, including intermediate-density lipoproteins and very low-density lipoprotein (VLDL) in the fasted state and celiac remnants in the non-fasted state [
18]. Studies have shown that RC is significantly associated with the development of T2DM and that higher levels of RC not only increase the risk of microvascular complications but may also lead to macrovascular complications in diabetes [
19‐
22]. In addition, recent studies have shown that RC predicts newly developed T2DM over traditional lipid parameters [
19,
23,
24]. Based on these findings, we hypothesized that cholesterol levels, including RC, during early pregnancy might also be associated with GDM. Unfortunately, only a limited number of studies have explored the relationship between cholesterol parameters, especially RC, in early pregnancy and the risk of GDM. Therefore, a secondary analysis was conducted using published data to elucidate the association between cholesterol parameters and the risk of GDM.
Discussion
This prospective cohort study of 590 pregnant women examined the relationship between RC and GDM. The results found that RC was an independent risk factor for GDM in pregnant women but not for other cholesterol parameters, including HDL-c, LDL-c, and TC. The results of the sensitivity analysis further support a stable association between RC and the risk of GDM. We also demonstrated that RC can accurately predict GDM with an AUC of 0.8038 (0.7338–0.8738). RC was much superior to TG, HDL-c, TC, and LDL-c in predicting GDM in pregnant women. Therefore, RC may be an effective non-invasive method for predicting GDM.
Atherogenic dyslipidemia, characterized by elevated levels of TG, TG-rich lipoproteins, and decreased HDL-c levels, has been extensively studied in the context of cardiovascular disease [
20,
37‐
39]. The association between cholesterol and cardiovascular disease remains a topic of debate. Some studies have concluded that cholesterol is not directly associated with cardiovascular disease but rather with inflammation. Some studies suggest that in the presence of atherosclerotic dyslipidemia, the overproduction of TG-rich lipoproteins and inefficient lipolytic processing contribute to increased RC formation. This cholesterol-enriched TG-rich lipoprotein is more prone to accumulate in the arterial wall, leading to atherosclerosis and cardiovascular disease [
18,
40]. Conversely, other studies have concluded that cholesterol is not directly associated with cardiovascular disease but rather with inflammation [
41,
42].However, there is growing evidence that RC is associated with T2DM and overall glucose metabolism [
19,
24,
43,
44]. Considering that RC is one of the most prevalent patterns of lipid abnormalities in insulin-resistant states [
24,
45,
46], we hypothesize that RC may affect pancreatic β cells and overall glucose metabolism in pregnant women. The current study investigated the association of RC with GDM and concluded that RC is an independent risk factor for the development of GDM in pregnant women, rather than other cholesterol parameters, including LDL-c, HDL-c, and TC. These findings are consistent with previous studies in the general population. Previous studies have shown that RC is positively associated with the risk of T2DM. In a longitudinal cohort study from Korea, the multivariate-adjusted analysis suggested that participants in the fourth quartile of RC had a higher risk of T2DM compared to those in the first quartile of RC (hazard ratios HR = 1.95;95% CI1.93–1.97). The HR for the second quartile of RC was 1.25 (95% CI1.24–1.27) and 1.51 (95% CI1.50–1.53) for the third quartile [
19]. In addition, a single-center cohort study in China showed that higher RC levels were independently associated with an increased risk of new-onset diabetes (HR = 2.44, 95% CI 1.50–3.89) [
24]. This is a very clinically relevant finding that RC is an independent risk factor for GDM and may be a potential target for the prevention and treatment of GDM. Clarifying their relationship informs the optimization of GDM prevention in pregnant women and facilitates communication with patients' families. It also provides valuable risk factors for future GDM prediction modeling.
Consistent with numerous previous studies, we employed the calculation of RC by subtracting HDL-c and LDL-c from TC, following the 2019 European Atherosclerosis Society guidelines for dyslipidemia management [
21,
27,
47,
48]. Our study revealed a statistically significant difference in the association between RC and GDM when employing this simple calculation. However, none of the variables in the formula, including TC, LDL-c, and HDL-c, exhibited a significant difference in their association with GDM risk. Several possible reasons account for this discrepancy. Firstly, as suggested by Jepsen et al., calculated RC tends to slightly overestimate the directly measured values. Nonetheless, calculated RC remains closely linked to measured RC, and the advantage of the RC approximation lies in its wide availability and cost-effectiveness [
17,
49]. Calculated RC can serve as a suitable alternative to measured RC for assessing the risk of various clinical outcomes [
49]. However, it must be emphasized that the calculated RC remains essentially the cholesterol of all triglyceride-rich (TG) lipoproteins. There is growing evidence that abnormalities in TG, TG-rich lipoproteins, are associated with T2DM and overall glucose metabolism [
43]. Studies have confirmed that elevated TG is strongly associated with an increased risk of GDM [
50,
51]. Our study likewise confirmed a significant positive association between TG and the risk of GDM. Thus, the involvement of TG may be a reason for the significant positive association of RC with GDM. Secondly, the fact that RC remains cholesterol-specific in nature, it is more harmful to pancreatic β-cells because of its higher cholesterol content, quantity, and volume compared to LDL-c [
52]. Additionally, RC may influence GDM through the inflammatory pathway, distinguishing it from conventional cholesterol. A study has provided evidence that elevated RC is causally associated with low-grade inflammation and ischemic heart disease (IHD), while elevated LDL-c is causally associated with IHD but not inflammation [
53].
Previous studies have shown that in the general population, TG, HDL-c, and TC in the conventional lipid profile are good lipid parameters for predicting the risk of diabetes mellitus [
24,
54,
55]. In the present study, HLR, LDL-c, TG, HDL-c, TC, and RC were calculated by ROC analysis in pregnant women at 12–14 weeks of gestation for their ability to predict GDM. The results showed that the area under the curve of RC was larger than other conventional lipid parameters. This suggests that RC may be a better indicator of glucose metabolism disorders in pregnant women and that measuring RC may help to predict pregnant women prone to GDM, especially those with normal HDL-c, LDL-c, and TC that are easily overlooked. When a pregnant woman's RC is greater than 24.3 mg/dL in early pregnancy, she has a high likelihood of developing GDM.
The underlying mechanism of the association between RC and GDM in pregnant women remains unclear. Insulin resistance may be the most critical factor. A study of residents in a rural community showed that fasting RC was strongly associated with IR [
46]. In another study, postprandial RC was an independent predictor of IR, regardless of BMI, age, and other lipid profiles [
56]. Additionally, RC may directly cause β-cell malfunction, which in turn causes insulin secretion suppression [
57], and this may be one of the potential mechanisms of their relationship. Furthermore, the human placenta is an important site for the conversion of cholesterol to steroids, and the biosynthesis of placental steroids is essential for pregnancy maintenance and embryonic development [
58]. In turn, a state of IR is induced in the second half of pregnancy by placental hormones such as placental-derived hormones, human placental lactogen, and human placental growth hormone [
59,
60]. This may also be one of the mechanisms by which elevated RC in early gestation is associated with an increased risk of GDM.
There are several strengths to note in this investigation. (i) the study is the first in confirming the independent association between early plasma RC levels in pregnant women and GDM and making comparisons with concerns between other cholesterol parameters and GDM; (ii) our study provides an AUROC and optimal threshold for early prediction of GDM by RC; (iii) To ensure the robustness of the conclusions, a series of sensitivity analyses were performed, including the conversion of RC to a categorical variable, reanalysis of the association between RC and onset GDM after excluding participants with BMI ≥ 25 kg/m2 and hepatic steatosis greater than or equal to grade 1, subgroup analysis and calculation of E values to explore the possibility of unmeasured confounders.
The present study does have certain limitations. First, because the association between RC and GDM may vary by race, our findings should be further validated in different ethnic groups. Second, because this study was a secondary analysis, it was impossible to adjust for factors not in the original data set, such as waist circumference, family history of diabetes, and hypertension. In addition, the present study did not adjust for inflammatory markers such as platelet-activating factor, C-reactive protein, etc., and analyze their relationship with the risk of GDM. In the future, we can think about how to design our study, and we will obtain more precise data on variables, including some inflammatory mediators. The third drawback is that RC was collected only once at 12–14 weeks of gestation. Therefore, we do not know if the RC changes after 14 weeks. This is an important- issue that may require further study. Fourth, this observational study did not demonstrate a causal relationship between RC and GDM; rather, it only established an association. Finally, even if possible confounders were adjusted for, as with all observational research, there could still be unmeasured or uncontrolled confounders. We calculated E-value, nevertheless, and discovered that unmeasured or uncontrolled confounders had no impact on our results.
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